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.
Highlights
There is a clinical need to identify novel treatments for lymphoid malignancies [1]
We have recently demonstrated that chronic lymphocytic leukemia (CLL) lymph nodes show salient features of non-inflamed tumors including sparse numbers of CD8+ T cells relative to reactive non-malignant tissues and low PD-L1 expression in the tumor microenvironment (TME), as well as profound T cell functional exhaustion [67]
Increased proliferation of VEGFR-1+ neovasculature has been observed in aggressive lymphomas (DLBCL and Burkitt’s lymphoma), and an elevated numbers of aSMA+ mesenchymal cells described in indolent non-Hodgkin lymphomas (NHLs) including CLL and small lymphocytic lymphoma (SLL) [231]
Summary
There is a clinical need to identify novel treatments for lymphoid malignancies [1]. Effective immunotherapy promotes the killing of cancer cells by cytotoxic T cells. The frequency of classical CD14+ HLA-DR+ monocytes prior to therapy was found to be a strong predictor of response, thought to reflect myeloid expansion triggered by IFNg produced by activated tumor-specific and infiltrated T cells in patients who are more likely to become responders Inflamed lymphomas such as cHL tumors have shown increased sensitivity to anti-PD-1 blockade therapy and are characterized by an unusually high immune cell infiltrate, an inflammatory PD-L1+ TME, a high mutational burden [95] and genetic alterations that facilitate cancer immunoediting escape including aberrant MHC class I molecule expression [96]. Recent studies have demonstrated that metabolically active tumor cells chronically deprive the TME of essential nutrients that affect T cell effector function and promote the creation of a tolerogenic TME [metabolic reprogramming in the lymphomas has been reviewed elsewhere [169,170,171]]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
