Hematopoietic versus Solid Cancers and T Cell Dysfunction: Looking for Similarities and Distinctions

Abstract

Cancer cells escape, suppress and exploit the host immune system to sustain themselves, and the tumor microenvironment (TME) actively dampens T cell function by various mechanisms. Over the last years, new immunotherapeutic approaches, such as adoptive chimeric antigen receptor (CAR) T cell therapy and immune checkpoint inhibitors, have been successfully applied for refractory malignancies that could only be treated in a palliative manner previously. Engaging the anti-tumor activity of the immune system, including CAR T cell therapy to target the CD19 B cell antigen, proved to be effective in acute lymphocytic leukemia. In low-grade hematopoietic B cell malignancies, such as chronic lymphocytic leukemia, clinical outcomes have been tempered by cancer-induced T cell dysfunction characterized in part by a state of metabolic lethargy. In multiple myeloma, novel antigens such as BCMA and CD38 are being explored for CAR T cells. In solid cancers, T cell-based immunotherapies have been applied successfully to melanoma and lung cancers, whereas application in e.g., breast cancer lags behind and is modestly effective as yet. The main hurdles for CAR T cell immunotherapy in solid tumors are the lack of suitable antigens, anatomical inaccessibility, and T cell anergy due to immunosuppressive TME. Given the wide range of success and failure of immunotherapies in various cancer types, it is crucial to comprehend the underlying similarities and distinctions in T cell dysfunction. Hence, this review aims at comparing selected, distinct B cell-derived versus solid cancer types and at describing means by which malignant cells and TME might dampen T cell anti-tumor activity, with special focus on immunometabolism. Drawing a meaningful parallel between the efficacy of immunotherapy and the extent of T cell dysfunction will shed light on areas where we can improve immune function to battle cancer.

A novel anti-B7-H3 chimeric antigen receptor from a single-chain antibody library for immunotherapy of solid cancers

“…Of note, hematological malignancies, especially leukemias, may display differences in their microenvironment compared with solid tumors that influence T cell persistence. 46 TE9-CD28 CAR also maintained significantly greater proliferation over 4 weeks of re-stimulation compared with the anti-GD2-CAR. 30 This was the primary reason TE9 was selected as our lead binder.…”

Epstein–Barr Virus—Associated Malignancies and Immune Escape: The Role of the Tumor Microenvironment and Tumor Cell Evasion Strategies

“…It has been well established that cells of the innate and adaptive immune system are able to recognize and eliminate cancer cells. However, the processes of malignant and/or viral transformation, as well as increased growth, are associated with strategies of tumor cells to escape immune surveillance [223] by evading the immune surveillance and/or by suppressing the hosts' immune system mediated by shaping the TME and dampening the effector function [224,225]. Indeed, tumor cells can convert immune cells to a tolerogenic and dysfunctional state due to cell-cell interactions, soluble mediators and physical factors in the TME.…”

“…These factors contribute to the disease prognosis and prediction of therapy response thereby exerting a clinical relevance [126]. Interestingly, there exist similarities but also differences between the immune escape strategies of solid and hematopoietic EBV-associated tumors [143,224].…”

Secondary Immunodeficiency in Hematological Malignancies: Focus on Multiple Myeloma and Chronic Lymphocytic Leukemia

“…Nevertheless, other immunologic alterations are verifiable in these subjects generally due to the same disease or to the treatment (116)(117)(118)(119)(120)(121)(122).…”