Lymphoma Microenvironment and Immunotherapy

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Abstract

Understanding of the lymphoma tumor microenvironment is poised to expand in the era of next-generation sequencing studies of the tumor cells themselves. Successful therapies of the future will rely on deeper appreciation of the interactions between elements of the microenvironment. Although the phenotypic, cytogenetic, and molecular characterization of tumor cells in lymphomas has progressed faster than most other solid organ tumors, concrete advancements in understanding the lymphoma microenvironment have been fewer. This article explores the composition of the lymphoma tumor microenvironment; its role in immune surveillance, evasion, and drug resistance; and its potential role in the development of targeted therapies.

Section snippets

Overview

Tumor microenvironment was initially addressed in the context of carcinoma metastases by Stephen Paget in 1889.1 In examining the pattern of breast cancer metastases at autopsy, he found that some organs demonstrated a preponderance of metastases and generated the hypothesis that “seeds,” or neoplastic cells, could only land and flourish in appropriate “soil,” or microenvironment. Decades later, scientists discovered that lung-homing melanoma cells, when implanted in mice, selectively

Tumor microenvironment in lymphoma

The key constituents of the lymphoma microenvironment and their pattern of distribution within tissue vary widely between tumors depending on the host inflammatory response as well as the genetics and proliferation rate of malignant cells (Box 1). For example, in tumors such as classic Hodgkin Lymphoma, polymorphic post-transplant lymphoproliferative disorders, and angioimmunoblastic T-cell lymphoma, the background non-neoplastic inflammatory components are prominent and often display typical

Chronic lymphocytic leukemia

Chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia cells disrupt the normal lymphoid architecture and show a distinctive morphology, often composed of pseudofollicles or proliferation centers that contain numerous prolymphocytes. This complete disruption of the normal microenvironment could explain the often associated immune deficiency and hypogammaglobulinemia seen in CLL patients.15

The tumor cells themselves express high levels of CXCR4 (the receptor for CXCL12) and tumor necrosis

Microenvironment-targeted immunotherapies for chronic lymphocytic leukemia

  • CXCR4 antagonists: blocks CLL cell trafficking and homing to marrow through interaction of CXCR4 with CXCL12 (eg, plerixafor [AMD3100] and T140 analogs)

  • TACI decoy receptor: soluble TACI presumed to buffer APRIL and BAFF. Early studies in patients with refractory or relapsed CLL seem to suggest that the drug antagonizes the proliferation of CLL cells (eg, Atacicept).

  • PI3K inhibitor: targets PI3K signaling in CLL, is thought to interfere with stromal cell interactions, releasing CLL tumor cells

Follicular lymphoma

Follicular lymphoma primarily occurs in lymph nodes, hijacking the normal follicle architecture. Compared with the normal lymph node, follicular lymphomas demonstrate increased Tregs and decreased effector T cells. Although earlier studies suggested that elevated numbers of Tregs predicted better survival in follicular lymphoma,19 more recent studies have pointed to the importance of its localization. In a study using consistent treatment regimens, patients with predominantly follicular pattern

Microenvironment-targeted immunotherapies for follicular lymphoma

  • PD-1 blocking antibody: disrupts interaction between immune checkpoint receptor PD-1 with its ligands PD-L1 and PD-L2, to prevent antitumor immunity (eg, nivolumab)

  • Anti-CTLA4 antibody: CTLA4 signaling from T cells down-regulate T-cell activity and induces T-cell cycle arrest. Blocking CTLA4 promotes activation of infiltrating T cells within tumor (eg, ipilimumab).

  • PI3K inhibitor: inhibits tumor cell migration, growth, angiogenesis (eg, idelalisib)

  • Proteasome inhibitor: ubiquitin-proteasome

Classic Hodgkin lymphoma

Hodgkin Reed-Sternberg (HRS) cells of classic Hodgkin lymphoma seem to secrete and induce the secretion of a wide variety of chemokines and cytokines that maintain the polymorphous background cellularity richly composed of stromal cells, fibroblasts, plasma cells, numerous T cells, eosinophils, and neutrophils. For example, HRS cells secrete colony-stimulating factor 1 (CSF1) and CX3CL1, which may help recruit abundant macrophages. Recent findings that CSF1 receptor-enriched microenvironment

Microenvironment-targeted immunotherapies for classic Hodgkin lymphoma

  • Histone deacetylace inhibitors: down-regulate PD-1 expression, stimulate antigen-specific memory T cells (eg, vorinostat and pabinostat)

  • PD-1 blocking antibody: disrupts interaction between immune checkpoint receptor PD-1 with its ligands PD-L1 and PD-L2, to prevent antitumor immunity (eg, nivolumab)

  • Anti-CTLA4 antibody: CTLA4 signaling from T cells down-regulate T-cell activity and induces T-cell cycle arrest. Blocking CTLA4 promotes activation of infiltrating T cells within tumor (eg,

Summary

Understanding of the lymphoma tumor microenvironment is poised to expand in the era of next-generation sequencing studies of the tumor cells themselves. For example, in diffuse large B-cell lymphomas, loss-of-function mutations in B2M and CD58 as well as focal deletions in TNFSF9 have been demonstrated by RNA sequencing and exome sequencing.34 B2M encodes a polypeptide β2-microglobulin that helps form MHC class I. The latter functions to present antigens to cytotoxic T cells in immune

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