Abstract
Although CAR T cell therapies have proven to be effective in treating hematopoietic cancers, their abilities to regress solid tumors have been less encouraging. Mechanisms to explain these disparities have focused primarily on differences in cancer cell heterogeneity, barriers to CAR T cell penetration of solid tumors, and immunosuppressive microenvironments. To evaluate the contributions of immunosuppressive tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) on CAR T cell efficacies, we have exploited the ability of a folate-targeted Toll-like receptor 7 agonist (FA-TLR7-1A) to specifically reactivate TAMs and MDSCs from an immunosuppressive to pro-inflammatory phenotype without altering the properties of other immune cells. We report here that FA-TLR7-1A significantly augments standard CAR T cell therapies of 4T1 solid tumors in immune competent mice. We further show that co-administration of the FA-TLR7-1A with the CAR T cell therapy not only repolarizes TAMs and MDSCs from an M2-like anti-inflammatory to M1-like pro-inflammatory phenotype, but also enhances both CAR T cell and endogenous T cell accumulation in solid tumors while concurrently increasing their states of activation. Because analogous myeloid cells in healthy tissues ar not altered by administration of FA-TLR7-1A, no systemic activation of the immune system nor accompanying weight loss is observed. These data argue that immunosuppressive myeloid cells contribute prominently to the failure of CAR T cells to eradicate solid tumors and suggest that methods to reprogram tumor associated myeloid cells to a more inflammatory phenotype could significantly augment the potencies of CAR T cell therapies.
Highlights
CAR T cell therapies have revolutionized the treatment of hematopoietic cancers by focusing the cytotoxic potential of a patient’s T cells on his/her cancer cells [1]
For evaluation of the impact of TLR7 agonist-mediated repolarization of tumor associated macrophage (TAM) and myeloid-derived suppressor cell (MDSC) on the efficacy of CAR T cell therapies in solid tumors, we required a cancer cell line that would be devoid of both folate receptors and TLR7, so that our FA-TLR7-1A conjugate could neither bind nor directly stimulate the implanted cancer cells
Since the hypothesis underpinning this study was that TLR71A-mediated stimulation of TAMs and MDSCs might enhance CAR T cell efficacy by shifting the tumor microenvironment (TME) towards a more inflammatory state, we examined whether the immune cells in the TME might have acquired a more inflammatory phenotype upon FA-TLR7-1A administration
Summary
CAR T cell therapies have revolutionized the treatment of hematopoietic cancers by focusing the cytotoxic potential of a patient’s T cells on his/her cancer cells [1]. CAR T cell inactivation may stem from multiple immunosuppressive stimuli, tumor-associated macrophages (TAMs) and myeloidderived suppressor cells (MDSCs) are thought to contribute prominently, since they i) secrete immunosuppressive cytokines (e.g. IL-10 and TGF-b) [3, 4], ii) nitrosylate and inactivate T cell receptors [5, 6], iii) express immune checkpoint receptors [7], iv) promote deposition of a dense extracellular matrix that can impede penetration of immune cells [8, 9], and v) produce immunosuppressive enzymes such as arginase 1, CD39 and 5’-nucleotidase [10,11,12] Based on these activities and data showing an inverse relationship between TAM/MDSC abundances and patient survival [13,14,15], it is not surprising that efforts to inhibit the immunosuppressive activities of TAMs/MDSCs are increasing [16]. Upon endocytosis by TAMs and MDSCs, the folate-TLR7a conjugate (FA-TLR7a) is observed to engage an endosomal Toll-like receptor 7 and initiate signaling pathways that reprogram the TAM/MDSCs into proinflammatory M1-like myeloid cells [17, 22]
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