Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma

Gabriel K. Griffin; Jason L. Weirather; Margaretha G. M. Roemer; Mikel Lipschitz; Alyssa Kelley; Pei-Hsuan Chen; Daniel Gusenleitner; Erin Jeter; Christine Pak; Evisa Gjini; Bjoern Chapuy; Michael H. Rosenthal; Jie Xu; Benjamin J. Chen; Aliyah R. Sohani; Scott B. Lovitch; Jeremy S. Abramson; Jeffrey J. Ishizuka; Austin I. Kim; Caron A. Jacobson; Ann S. LaCasce; Christopher D. Fletcher; Donna Neuberg; Gordon J. Freeman; F. Stephen Hodi; Kyle Wright; Azra H. Ligon; Eric D. Jacobsen; Philippe Armand; Margaret A. Shipp; Scott J. Rodig

doi:10.1182/blood.2020006464

Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma

Gabriel K. Griffin, Jason L. Weirather, Margaretha G. M. Roemer, Mikel Lipschitz, Alyssa Kelley, Pei-Hsuan Chen, Daniel Gusenleitner, Erin Jeter, Christine Pak, Evisa Gjini, Bjoern Chapuy, Michael H. Rosenthal, Jie Xu, Benjamin J. Chen, Aliyah R. Sohani, Scott B. Lovitch, Jeremy S. Abramson, Jeffrey J. Ishizuka, Austin I. Kim, Caron A. JacobsonAnn S. LaCasce, Christopher D. Fletcher, Donna Neuberg, Gordon J. Freeman, F. Stephen Hodi, Kyle Wright, Azra H. Ligon, Eric D. Jacobsen, Philippe Armand, Margaret A. Shipp, Scott J. Rodig^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune “neighborhoods” in which malignant B cells are surrounded by exceptionally high numbers of PD-L1–expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types. Key Points: • Spatially resolved signatures of PD-1/PD-L1 signaling in the tumor microenvironment define T-cell/histiocyte-rich large B-cell lymphoma. • Three of 5 patients with relapsed/refractory TCRLBCL showed objective clinical responses to single-agent PD-1 blockade (pembrolizumab).

Original language	English
Pages (from-to)	1353-1364
Number of pages	12
Journal	Blood
Volume	137
Issue number	10
DOIs	https://doi.org/10.1182/blood.2020006464
Publication status	Published - 11 Mar 2021

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10.1182/blood.2020006464

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Griffin, G. K., Weirather, J. L., Roemer, M. G. M., Lipschitz, M., Kelley, A., Chen, P-H., Gusenleitner, D., Jeter, E., Pak, C., Gjini, E., Chapuy, B., Rosenthal, M. H., Xu, J., Chen, B. J., Sohani, A. R., Lovitch, S. B., Abramson, J. S., Ishizuka, J. J., Kim, A. I., ... Rodig, S. J. (2021). Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma. Blood, 137(10), 1353-1364. https://doi.org/10.1182/blood.2020006464

@article{7a18c2f6cb694cf9830d05bc16763cf4,

title = "Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma",

abstract = "T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune “neighborhoods” in which malignant B cells are surrounded by exceptionally high numbers of PD-L1–expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types. Key Points: • Spatially resolved signatures of PD-1/PD-L1 signaling in the tumor microenvironment define T-cell/histiocyte-rich large B-cell lymphoma. • Three of 5 patients with relapsed/refractory TCRLBCL showed objective clinical responses to single-agent PD-1 blockade (pembrolizumab).",

author = "Griffin, {Gabriel K.} and Weirather, {Jason L.} and Roemer, {Margaretha G. M.} and Mikel Lipschitz and Alyssa Kelley and Pei-Hsuan Chen and Daniel Gusenleitner and Erin Jeter and Christine Pak and Evisa Gjini and Bjoern Chapuy and Rosenthal, {Michael H.} and Jie Xu and Chen, {Benjamin J.} and Sohani, {Aliyah R.} and Lovitch, {Scott B.} and Abramson, {Jeremy S.} and Ishizuka, {Jeffrey J.} and Kim, {Austin I.} and Jacobson, {Caron A.} and LaCasce, {Ann S.} and Fletcher, {Christopher D.} and Donna Neuberg and Freeman, {Gordon J.} and Hodi, {F. Stephen} and Kyle Wright and Ligon, {Azra H.} and Jacobsen, {Eric D.} and Philippe Armand and Shipp, {Margaret A.} and Rodig, {Scott J.}",

note = "Funding Information: Conflict-of-interest disclosure: G.K.G. has been a consultant for Moderna Therapeutics. J.J.I. has been a consultant for Tango Therapeutics and Phenomic AI. A.H.L. has served on a Data Safety Monitoring Board for BMS. P.A. has been a consultant for Merck, BMS, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, Miltenyi, Tessa, GenMab, C4, and Enterome; and has received research funding (institutional) from Merck, BMS, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma Tau, Genentech, and IGM and honoraria from Merck and BMS. G.J.F. has patents/pending royalties on the PD-1/PD-L1 pathway from Roche, Merck MSD, Bristol-Myers-Squibb, Merck KGA, Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, and Jubilant and has equity in Nextpoint, Triursus, Xios, and IgM. J.S.A. has been a consultant for Abbvie, Allogene, C4 Therapeutics, Celgene, EMD Serono, Karyopharm, Kite Pharm, Merck, Morphosys, Novartis, and Roche. F.S.H. reports institutional funding from Bristol-Myers Squibb during the conduct of the study; grants, personal fees, and other remuneration from Bristol-Myers Squibb and Novartis; personal fees from Merck, EMD Serono, Takeda, Surface, Genentech/Roche, Compass Therapeutics, Apricity, Bayer, Aduro, Partners Therapeutics, Sanofi, Pfizer, Pionyr, 7 Hills Pharma, Verastem, Torque, Rheos, Kairos, Bicara, Psioxus Therapeutics, and Amgen; and other remuneration from Pieris Pharmacutical, Boston Pharmaceuticals, and Zumutor, outside the submitted work; and patents “Methods for Treating MICA-Related Disorders” (no. 20100111973), with royalties paid; “Tumor Antigens and Uses Thereof (no. 7250291), issued; “Angiopoiten-2 Biomarkers Predictive of Anti-immune Checkpoint Response” (no. 20170248603), pending; “Copositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma Using PD-L1 Isoforms” (no. 20160340407), pending; “Therapeutic Peptides” (no. 20160046716), pending; “Therapeutic Peptides” (no. 20140004112), pending; “Therapeutic Peptides” (no. 20170022275), pending; “Therapeutic Peptides” (no. 20170008962), pending; “Therapeutic Peptides” (no. 9402905), issued; “Methods of Using Pembrolizumab and Trebananib” (no. 2019028012), pending; “Vaccine Compositions and Methods for Restoring NKG2D Pathway Function against Cancers” (no. 10279021), issued; and “Antibodies that Bind to MHC class I Polypeptide-Related Sequence A” (no. US10106611), issued. S.J.R. has received research support from Bristol-Myers Squibb, Merck, Affimed, and KITE/Gilead, and has been a member of the Science Advisory Boards for KITE/Gilead and Immunitas. The remaining authors declare no competing financial interests. Funding Information: This work was supported by National Institutes of Health, National Heart, Lung, and Blood Institute T32 training grant HL007627; the Stanley L. Robbins Memorial Research Fund Award within the Department of Pathology, Brigham and Women's Hospital (both G.K.G.); and the Center for Immuno-Oncology, the Dana-Farber Cancer Institute. Publisher Copyright: {\textcopyright} 2021 American Society of Hematology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.",

year = "2021",

month = mar,

day = "11",

doi = "10.1182/blood.2020006464",

language = "English",

volume = "137",

pages = "1353--1364",

journal = "Blood",

issn = "0006-4971",

publisher = "American Society of Hematology",

number = "10",

}

Griffin, GK, Weirather, JL, Roemer, MGM, Lipschitz, M, Kelley, A, Chen, P-H, Gusenleitner, D, Jeter, E, Pak, C, Gjini, E, Chapuy, B, Rosenthal, MH, Xu, J, Chen, BJ, Sohani, AR, Lovitch, SB, Abramson, JS, Ishizuka, JJ, Kim, AI, Jacobson, CA, LaCasce, AS, Fletcher, CD, Neuberg, D, Freeman, GJ, Hodi, FS, Wright, K, Ligon, AH, Jacobsen, ED, Armand, P, Shipp, MA & Rodig, SJ 2021, 'Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma', Blood, vol. 137, no. 10, pp. 1353-1364. https://doi.org/10.1182/blood.2020006464

TY - JOUR

T1 - Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma

AU - Griffin, Gabriel K.

AU - Weirather, Jason L.

AU - Roemer, Margaretha G. M.

AU - Lipschitz, Mikel

AU - Kelley, Alyssa

AU - Chen, Pei-Hsuan

AU - Gusenleitner, Daniel

AU - Jeter, Erin

AU - Pak, Christine

AU - Gjini, Evisa

AU - Chapuy, Bjoern

AU - Rosenthal, Michael H.

AU - Xu, Jie

AU - Chen, Benjamin J.

AU - Sohani, Aliyah R.

AU - Lovitch, Scott B.

AU - Abramson, Jeremy S.

AU - Ishizuka, Jeffrey J.

AU - Kim, Austin I.

AU - Jacobson, Caron A.

AU - LaCasce, Ann S.

AU - Fletcher, Christopher D.

AU - Neuberg, Donna

AU - Freeman, Gordon J.

AU - Hodi, F. Stephen

AU - Wright, Kyle

AU - Ligon, Azra H.

AU - Jacobsen, Eric D.

AU - Armand, Philippe

AU - Shipp, Margaret A.

AU - Rodig, Scott J.

N1 - Funding Information: Conflict-of-interest disclosure: G.K.G. has been a consultant for Moderna Therapeutics. J.J.I. has been a consultant for Tango Therapeutics and Phenomic AI. A.H.L. has served on a Data Safety Monitoring Board for BMS. P.A. has been a consultant for Merck, BMS, Pfizer, Affimed, Adaptive, Infinity, ADC Therapeutics, Celgene, Morphosys, Daiichi Sankyo, Miltenyi, Tessa, GenMab, C4, and Enterome; and has received research funding (institutional) from Merck, BMS, Affimed, Adaptive, Roche, Tensha, Otsuka, Sigma Tau, Genentech, and IGM and honoraria from Merck and BMS. G.J.F. has patents/pending royalties on the PD-1/PD-L1 pathway from Roche, Merck MSD, Bristol-Myers-Squibb, Merck KGA, Boehringer-Ingelheim, AstraZeneca, Dako, Leica, Mayo Clinic, and Novartis. G.J.F. has served on advisory boards for Roche, Bristol-Myers-Squibb, Xios, Origimed, Triursus, iTeos, NextPoint, IgM, and Jubilant and has equity in Nextpoint, Triursus, Xios, and IgM. J.S.A. has been a consultant for Abbvie, Allogene, C4 Therapeutics, Celgene, EMD Serono, Karyopharm, Kite Pharm, Merck, Morphosys, Novartis, and Roche. F.S.H. reports institutional funding from Bristol-Myers Squibb during the conduct of the study; grants, personal fees, and other remuneration from Bristol-Myers Squibb and Novartis; personal fees from Merck, EMD Serono, Takeda, Surface, Genentech/Roche, Compass Therapeutics, Apricity, Bayer, Aduro, Partners Therapeutics, Sanofi, Pfizer, Pionyr, 7 Hills Pharma, Verastem, Torque, Rheos, Kairos, Bicara, Psioxus Therapeutics, and Amgen; and other remuneration from Pieris Pharmacutical, Boston Pharmaceuticals, and Zumutor, outside the submitted work; and patents “Methods for Treating MICA-Related Disorders” (no. 20100111973), with royalties paid; “Tumor Antigens and Uses Thereof (no. 7250291), issued; “Angiopoiten-2 Biomarkers Predictive of Anti-immune Checkpoint Response” (no. 20170248603), pending; “Copositions and Methods for Identification, Assessment, Prevention, and Treatment of Melanoma Using PD-L1 Isoforms” (no. 20160340407), pending; “Therapeutic Peptides” (no. 20160046716), pending; “Therapeutic Peptides” (no. 20140004112), pending; “Therapeutic Peptides” (no. 20170022275), pending; “Therapeutic Peptides” (no. 20170008962), pending; “Therapeutic Peptides” (no. 9402905), issued; “Methods of Using Pembrolizumab and Trebananib” (no. 2019028012), pending; “Vaccine Compositions and Methods for Restoring NKG2D Pathway Function against Cancers” (no. 10279021), issued; and “Antibodies that Bind to MHC class I Polypeptide-Related Sequence A” (no. US10106611), issued. S.J.R. has received research support from Bristol-Myers Squibb, Merck, Affimed, and KITE/Gilead, and has been a member of the Science Advisory Boards for KITE/Gilead and Immunitas. The remaining authors declare no competing financial interests. Funding Information: This work was supported by National Institutes of Health, National Heart, Lung, and Blood Institute T32 training grant HL007627; the Stanley L. Robbins Memorial Research Fund Award within the Department of Pathology, Brigham and Women's Hospital (both G.K.G.); and the Center for Immuno-Oncology, the Dana-Farber Cancer Institute. Publisher Copyright: © 2021 American Society of Hematology Copyright: Copyright 2021 Elsevier B.V., All rights reserved.

PY - 2021/3/11

Y1 - 2021/3/11

N2 - T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune “neighborhoods” in which malignant B cells are surrounded by exceptionally high numbers of PD-L1–expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types. Key Points: • Spatially resolved signatures of PD-1/PD-L1 signaling in the tumor microenvironment define T-cell/histiocyte-rich large B-cell lymphoma. • Three of 5 patients with relapsed/refractory TCRLBCL showed objective clinical responses to single-agent PD-1 blockade (pembrolizumab).

AB - T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune “neighborhoods” in which malignant B cells are surrounded by exceptionally high numbers of PD-L1–expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types. Key Points: • Spatially resolved signatures of PD-1/PD-L1 signaling in the tumor microenvironment define T-cell/histiocyte-rich large B-cell lymphoma. • Three of 5 patients with relapsed/refractory TCRLBCL showed objective clinical responses to single-agent PD-1 blockade (pembrolizumab).

UR - http://www.scopus.com/inward/record.url?scp=85102606515&partnerID=8YFLogxK

U2 - 10.1182/blood.2020006464

DO - 10.1182/blood.2020006464

M3 - Article

C2 - 32871584

VL - 137

SP - 1353

EP - 1364

JO - Blood

JF - Blood

SN - 0006-4971

IS - 10

ER -

Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma

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