Immunosuppressive Strategies that are Mediated by Tumor Cells

Abstract

Despite major advances toward an improved understanding of the mechanisms leading to tumor immunity, the successful translation of mechanistic insights into effective tumor immunotherapy is hindered by a number of immunological obstacles. These include the ability of tumors to foster a tolerant microenvironment and the activation of a plethora of immunosuppressive mechanisms, which may act in concert to counteract effective immune responses. Here we will discuss different strategies employed by tumors to thwart immune responses, including tumor-induced impairment of antigen presentation, activation of negative costimulatory signals and elaboration of immunosuppressive and pro-apopoptic factors. In addition, we will underscore the influence of regulatory cell populations that may contribute to this immunosuppressive network including regulatory T cells, NKT cells and distinct subsets of immature and mature dendritic cells. The current wealth of preclinical information promises a future scenario in which the synchronized blockade of immunosuppressive mechanisms and the removal of inhibitory signals might be effective in combination with other conventional strategies to overcome immunological tolerance and promote tumor regression.

Improving Chimeric Antigen Receptor-Modified T Cell Function by Reversing the Immunosuppressive Tumor Microenvironment of Pancreatic Cancer

“…19 Thus, to assess the proliferative capacity of CAR-PSCA T cells with prolonged exposure to immunosuppressive growth conditions, we stimulated cells weekly using irradiated K562-PSCA (1:1 E:T). Cultures were supplemented with either IL-2 (50 U/mL three times per week) or IL-4 (400 U/mL three times per week), and cell growth was assessed by weekly counting using trypan blue exclusion.…”

“…12 However, malignant cells comprise only 10%-40% of the tumor, 13,14 while the rest is a complex desmoplastic matrix consisting of extracellular proteins, stellate cells, and immunomodulatory cells that produce cytokines including interleukin-4 (IL-4), IL-10, and transforming growth factor b (TGF-b) that promote fibrogenesis, support tumor growth and protect malignant cells from immune destruction. [15][16][17][18][19][20] Thus, in order to provide clinical benefit to patients with PDAC, it is likely that the tumor-targeting T cells will require additional engineering to enable them to withstand this hostile environment.…”

Actin stabilizer TAGLN2 potentiates adoptive T cell therapy by boosting the inside-out costimulation via lymphocyte function-associated antigen-1

“…2 Simultaneously, cell-based immunotherapy has emerged as a highly promising approach for the treatment of cancer. 5 However, both strategies have limitations, including a lack of responsive in some patients, 2 difficulty in treating solid tumors, 4 and off-target toxicities. 1,4,7,44 Therefore, it is of great clinical interest to develop alternative methods to potentiate cancer cell therapy.…”

“…4 However, these approaches have not yet been transferred to solid tumors, due in part to the strong immunosuppressive tumor microenvironment that may protect them from immune attack. 5–7 It is therefore of great clinical interest to develop new strategies to potentiate the antitumor activities of reactivated TILs or CAR-engineered T and NK cells.…”

Effector CD8+ T cells activated in vitro confer immediate and long‐term tumor protection in vivo

“…However, immuno-evasive effects of the tumor [1,2] may also limit the success of immunization. An alternative method of immunotherapy is to isolate tumor-specific T cells from a patient, and to activate and expand them in vitro before transfer back into the patient.…”