Abstract
By promoting the cytotoxic function of CD8+ T cells, immune checkpoint inhibitor therapy, e.g. programmed cell death protein-1 (PD-1), effectively inhibits tumor growth in renal cell carcinoma. Yet, as many as 87% of cancer patients do not respond to immune checkpoint therapy. Importantly, cytotoxic CD8+ T cell function crucially relies on CD4+ T helper cell cytokines, in particular, tumor necrosis factor beta (TNFβ) and its CD8+ T cell receptor (TNFR2) in the opposing manner as immune checkpoints and their receptors. Remarkably, despite advances in immunotherapy, there are no pharmaceutical treatments that increase circulating CD4+ T cell counts. Nor has there been much attention given to tumor-infiltrating CD4+ T cells. Using data from a clinical trial (NCT01731691), we discovered that the protein alpha-1 proteinase inhibitor (α1PI, alpha-1 antitrypsin) regulates the number of circulating CD4+ T cells. The orally available small-molecule drug Alphataxin acts as a surrogate for α1PI in this pathway. We aimed to examine how Alphataxin affected tumor growth in a murine model of renal cell carcinoma. Alphataxin, in combination with anti-PD-1 antibody, significantly elevated the ratio of circulating and tumor-infiltrating CD4+ T cells. In one study, following orthotopic implantation of syngeneic renal adenocarcinoma cells, combination treatment resulted in 100% regression of tumor growth. Moreover, in mice implanted orthotopically with one log more tumor cells, doubling Alphataxin dose in combination treatment led to 100% regression in one-third of mice and 81% suppression of tumor growth in the remaining two-thirds of mice. Lung metastasis was present in monotherapy, but significantly reduced in combination-treated mice. Orally available Alphataxin, the first and only drug developed to increase CD4+ T cells, in combination with anti-PD-1, is a powerful therapeutic method that provides long-term remission in renal cell carcinoma and potentially other T cell-responsive cancers by increasing the number of CD4+ tumor-infiltrating T cells.
Highlights
The immune checkpoint protein programmed cell death protein1 (PD-1) expressed on CD4+ and CD8+ T cells and its ligand programmed death-ligand 1 (PD-L1) which is overexpressed by tumor cells are effective immune checkpoints that inhibit the cytotoxic function of CD8+ T lymphocytes (CTLs) transforming CTLs into exhausted T cells which are not well defined or possibly regulatory cells (Tregs) that suppress immune responses [1]
Monoclonal antibodies that bind to PD-1 or PD-L1 are immune checkpoint inhibitors that prevent this receptor-ligand interaction and allow CTLs to limit tumor growth and improve prognosis in multiple T cellresponsive cancers including renal adenocarcinoma by enhancing the cytotoxic, antitumor activity of CD8+ tumor infiltrating lymphocytes (TILs) [2,3,4,5,6]
CD4+ T cells release tumor necrosis factor beta (TNFb) which binds to its CD8+ T cell receptor (TNFR2) in the same manner, but with the opposite outcome, that tumor cells release immune checkpoints that bind to their CD8+ T cell receptors, e.g. PD-1 [12]
Summary
The immune checkpoint protein programmed cell death protein (PD-1) expressed on CD4+ and CD8+ T cells and its ligand programmed death-ligand 1 (PD-L1) which is overexpressed by tumor cells are effective immune checkpoints that inhibit the cytotoxic function of CD8+ T lymphocytes (CTLs) transforming CTLs into exhausted T cells which are not well defined or possibly regulatory cells (Tregs) that suppress immune responses [1]. Monoclonal antibodies that bind to PD-1 or PD-L1 are immune checkpoint inhibitors that prevent this receptor-ligand interaction and allow CTLs to limit tumor growth and improve prognosis in multiple T cellresponsive cancers including renal adenocarcinoma by enhancing the cytotoxic, antitumor activity of CD8+ tumor infiltrating lymphocytes (TILs) [2,3,4,5,6]. Despite the efficacy of checkpoint inhibitors in promoting the cytotoxic activities of CD8+ TILs, as many as 87% of patients do not benefit from this treatment [7, 8]. As well as immune checkpoint inhibitors to enhance cytotoxic CD8+ TILs activity in the tumor microenvironment, tumor control requires CD4+ T helper cells to provide activating cytokines to CTLs [9]. There have been few investigations on the role of CD4+ TILs [9, 13]
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