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Abstract

Non-Hodgkin lymphoma (NHL) is a diverse category of hematological malignancies, and is the 5th most commonly diagnosed malignancy in the United States, with over 70,000 newly diagnosed cases every year1. The most common histological subtype of NHL is diffuse large B cell lymphoma (DLBCL), which comprises around 40% of all NHLs2. DLBCL is an extremely aggressive subtype of lymphoma, characterized by large sheets of malignant B cells that efface normal lymph node architecture. The standard of care treatment for DLBCL is R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone), a chemoimmunotherapy regimen that is curative in the majority of patients (~60%)4. However, the remaining 40% of patients with relapsed or refractory (r/r) DLBCL will eventually succumb to their disease. A significant hurdle in finding more effective treatments for DLBCL is the morphological, transcriptional, and genetic heterogeneity of the disease. However, recent advances in next-generation sequencing (NGS) technologies has enabled a more refined classification of DLBCL, and identified several novel therapeutic targets. In addition to targeted therapies, several immunotherapies – CAR T-cell therapy, bispecific antibodies (bsAbs), checkpoint blockade (CBT) – have also shown efficacy in subsets of patients with DLBCL5–12. A deeper understanding of the immune environment of DLBCL, and the molecular and cellular factors that regulate the immune environment, may expand the subset of patients with r/r DLBCL that will benefit from immunotherapies. Here, I show that DLBCLs are characterized by a spectrum of immune environments. These “hot” and “cold” environments are recurrently associated with several oncogenic alterations that may play a role in orchestrating the immune environment. For example, loss of function (LoF) mutations in SOCS1 – a negative regulator of IFN-driven JAK/STAT signaling – are recurrently associated with “hot” DLBCLs. In solid cancers, tumor cell-intrinsic sensitivity to IFN – a critical T cell derived effector cytokine- is a key determinant of response to immunotherapy. Therefore, SOCS1 mutant DLBCLs may represent a subset of “inflamed” DLBCLs that may be sensitive to T cell-based immunotherapies. Confirmatory studies in vitro and in vivo, using Socs1-deficient B cells and Socs1-deficient melanoma cells, show that genetic ablation of Socs1 may render cells more sensitive to IFN. In general, understanding the immune environment of DLBCL and how it affects the response to immunotherapies can aid in identifying patients who could benefit from such treatments. Moreover, uncovering intrinsic factors of lymphoma cells that regulate the immune environment could reveal new therapeutic targets that may complement immunotherapies and expand the pool of individuals who could benefit from them.

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