Regulation of antigen-specific T cell infiltration and spatial architecture in multiple myeloma and premalignancy
M. Hope Robinson, Nancy Y. Villa, David L. Jaye, Ajay K. Nooka, Alyssa Duffy, Samuel S. McCachren, Julia Manalo, Jeffrey M. Switchenko, Sierra Barnes, Sayalee Potdar, Maryam I. Azeem, Ava A. Horvat, Vaunita C. Parihar, Jingjing Gong, Yan Liang, Geoffrey H. Smith, Vikas A. Gupta, Lawrence H. Boise, Jonathan L. Kaufman, Craig C. Hofmeister, Nisha S. Joseph, Sagar Lonial, Kavita M. Dhodapkar, Madhav V. Dhodapkar
M. Hope Robinson, Nancy Y. Villa, David L. Jaye, Ajay K. Nooka, Alyssa Duffy, Samuel S. McCachren, Julia Manalo, Jeffrey M. Switchenko, Sierra Barnes, Sayalee Potdar, Maryam I. Azeem, Ava A. Horvat, Vaunita C. Parihar, Jingjing Gong, Yan Liang, Geoffrey H. Smith, Vikas A. Gupta, Lawrence H. Boise, Jonathan L. Kaufman, Craig C. Hofmeister, Nisha S. Joseph, Sagar Lonial, Kavita M. Dhodapkar, Madhav V. Dhodapkar
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Research Article Hematology Immunology

Regulation of antigen-specific T cell infiltration and spatial architecture in multiple myeloma and premalignancy

Abstract

Entry of antigen-specific T cells into human tumors is critical for immunotherapy, but the underlying mechanisms are poorly understood. Here, we combined high-dimensional spatial analyses with in vitro and in vivo modeling to study the mechanisms underlying immune infiltration in human multiple myeloma (MM) and its precursor monoclonal gammopathy of undetermined significance (MGUS). Clustered tumor growth was a feature of MM but not MGUS biopsies, and this growth pattern was reproduced in humanized mouse models. MM biopsies exhibited intralesional as well as spatial heterogeneity, with coexistence of T cell–rich and T cell–sparse regions and the presence of areas of T cell exclusion. In vitro studies demonstrated that T cell entry into MM clusters was regulated by agonistic signals and CD2-CD58 interactions. Upon adoptive transfer, antigen-specific T cells localized to the tumor site but required in situ DC–mediated antigen presentation for tumor entry. C-type lectin domain family 9 member A–positive (CLEC9A+) DCs appeared to mark portals of entry for gradients of T cell infiltration in MM biopsies, and their proximity to T cell factor 1–positive (TCF1+) T cells correlated with disease state and risk status. These data illustrate a role for tumor-associated DCs and in situ activation in promoting the infiltration of antigen-specific T cells in MM and provide insights into spatial alterations in tumor/immune cells with malignant evolution.

Authors

M. Hope Robinson, Nancy Y. Villa, David L. Jaye, Ajay K. Nooka, Alyssa Duffy, Samuel S. McCachren, Julia Manalo, Jeffrey M. Switchenko, Sierra Barnes, Sayalee Potdar, Maryam I. Azeem, Ava A. Horvat, Vaunita C. Parihar, Jingjing Gong, Yan Liang, Geoffrey H. Smith, Vikas A. Gupta, Lawrence H. Boise, Jonathan L. Kaufman, Craig C. Hofmeister, Nisha S. Joseph, Sagar Lonial, Kavita M. Dhodapkar, Madhav V. Dhodapkar

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Figure 7

Proposed models.

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Proposed models. (A) Cluster formation and immune changes with malignant...
(A) Cluster formation and immune changes with malignant transition. Evolution from MGUS to MM is accompanied by a tumor-intrinsic capacity to form clusters. This transition is accompanied by loss of TCF1+ stem memory–like T cells, increased GZMB+ effector T cells, as well as alterations in the myeloid compartment. Clustered tumor growth sets the stage for T cell exclusion and spatial immune escape during malignant transition. (B) Role for DC-mediated antigen presentation in T cell entry. The cancer immunity cycle, as initially proposed, consisted of an afferent phase involving the generation of antigen-specific T cells by DCs and an efferent phase involving killing of tumor cells by tumor-specific T cells. Data in this study support an additional role for tumor-associated DCs (red boxed area), where the entry of antigen-specific T cells into tumor clusters depends on antigen-specific activation of T cells in situ by professional APCs. Hence, T cell infiltration into MM tumors is not random but occurs through portals of entry and antigen presentation hotspots containing antigen-presenting DCs. TCF1+ T cells are found in proximity to CLEC9A+ DCs, and the proximity of these cell types correlates with disease stage and risk.