Understanding the Immune-Stroma Microenvironment in B Cell Malignancies for Effective Immunotherapy

Abstract

Cancers, including lymphomas, develop in complex tissue environments where malignant cells actively promote the creation of a pro-tumoral niche that suppresses effective anti-tumor effector T cell responses. Research is revealing that the tumor microenvironment (TME) differs between different types of lymphoma, covering inflamed environments, as exemplified by Hodgkin lymphoma, to non-inflamed TMEs as seen in chronic lymphocytic leukemia (CLL) or diffuse-large B-cell lymphoma (DLBCL). In this review we consider how T cells and interferon-driven inflammatory signaling contribute to the regulation of anti-tumor immune responses, as well as sensitivity to anti-PD-1 immune checkpoint blockade immunotherapy. We discuss tumor intrinsic and extrinsic mechanisms critical to anti-tumor immune responses, as well as sensitivity to immunotherapies, before adding an additional layer of complexity within the TME: the immunoregulatory role of non-hematopoietic stromal cells that co-evolve with tumors. Studying the intricate interactions between the immune-stroma lymphoma TME should help to design next-generation immunotherapies and combination treatment strategies to overcome complex TME-driven immune suppression.

Keywords: CAR T; T cells; anti-PD1; immunotherapy; interferon; lymphoma; stroma; tumor microenviroment.

Figure 1

The immune TME in B cell malignancies. Tumor intrinsic and tumor extrinsic mechanisms associated with noninflamed/cold () or inflamed/hot () TMEs in B cell malignancy. The key factors that shape the TME include tumor immunogenicity, oncogenic pathways and genetic alterations that regulate T cell infiltration and function. Note: the timeline or sequence of events during the evolution of the altered pro-tumor, yet immunoprivileged TME is a current topic in the field. Emerging evidence from patients treated with immune checkpoint blockade drugs suggests that cancer immunoediting takes place not only during tumor progression but also in response to therapy (e.g. the acquisition of mutations that contribute to ‘defective IFN signaling’) (–11). Several factors of immune escape and resistance to immunotherapy (innate or acquired) that have been characterized to date, can be broadly divided in tumor-intrinsic and tumor-extrinsic mechanisms. Tumor intrinsic mechanisms generally include genetic aberrations that can affect antigen recognition (‘loss/reduction of HLA-I/-II molecules’) (, –119) and influence immune function (‘PD-L1/2 upregulation’) (–122) and immune contexture in TMEs (‘oncogenic pathway deregulation’) including neoantigen load (83, 84). Tumor cell extrinsic factors that regulate anti-tumor immunity, immune evasion or resistance to immunotherapy involve non-tumor cellular and molecular components within the immune TME including ‘upregulation of inhibitory immune checkpoints’ (linked to chronic IFN signaling) (–125), the ‘recruitment of TAMs, MDSCs, T_Regs’ and stromal cells, as well as ‘deregulated cytokines and EVs’ (–130), ‘ineffective T cell priming’ and ‘T cell exclusion’ (–135). (Created with Biorender.com).

Figure 2

Stroma cells as key players in regulating immune responses in the TME of B cell malignancies. (A) Tumor cells and tissue-resident stroma (endothelial cells (ECs) and FRCs [fibroblastic reticular cells)/MSCs (mesenchymal stromal cells)] engage into complex bidirectional interactions that promote cancer progression while simultaneously altering the stroma cell phenotype which can then further contribute to resistance to therapy. Tumor B cells induce neoangiogensis and the upregulation of adhesion molecules on ECs (–245, 248, 252). Similarly, lymphoma cells through cell-to-cell contact interactions, secretion of soluble factors and extracellular vesicles (EVs) promote the activation of FRCs and MSCs that contribute to increased tumor survival and neoangiogensis (, –255). (B) Unlike solid tumors the investigation of the immunosuppressive roles of stroma cells in the lymphoma TME is still in its infancy. Stromal cells play a crucial role in spatial organization of the TME as they can retain immunoregulatory cells and possibly actively exclude anti-tumor effector cell populations (, , –261). Additionally, lymphoma ECs and FRCs upregulate immune checkpoints such as TIM-3 and PD-L1 (261, 262) and secrete immunoregulatory factors such as IDO and IL-10 that block T cell proliferation, while activating immunosuppressive cells (–266). FRCs have been also found to drive the survival of pro-tumoral immune subsets such as T_FH, T_H2 and TAMs (–260). (Created with Biorender.com).

Figure 3

Targeting strategies to activate anti-tumor immunity in the TME. Therapeutic strategies include re-activation of autologous anti-tumor immune responses using CELMoDs (e.g. avadomide) (67) or T-cell bispecific antibodies and fusion proteins (CD20-TCB, CD19-4-1BBL, Blinatumumab) (–282). Anti-tumor immunity can also be induced by transferring CAR-T/NK effector cells that directly target cancer cells (CD19-CAR-T) (283). In addition, cancer-associated stroma can be efficiently targeted to boost anti-tumor immunity, and fibroblasts-specific pharmacological approaches (anti-FAP antibodies or CAR-T) have been shown to induce tumor regression (284). Tumor stroma can also be ‘normalized’ by blocking or neutralizing cancer-secreted factors that promote stromal cell activation (Endostatin, Imatinib, anti-TGFβ) (–287). Moreover, the presence of cancer-stroma-specific proteins can be used to activate tissue resident anti-tumor T cells using stroma-specific/T cells co-stimulatory fusion proteins (FAP-4-1BBL) (282). (Created with Biorender.com).