Restoring Immune Function of Tumor-Specific CD4+ T Cells during Recurrence of Melanoma

Abstract

Recurrent solid malignancies are often refractory to standard therapies. While adoptive T cell transfer may benefit select individuals, the majority of patients succumb to their disease. In order to address this important clinical dilemma, we developed a mouse melanoma model in which initial regression of advanced disease was followed by tumor recurrence. During recurrence, Foxp3+ tumor-specific CD4+ T cells became PD-1+ and represented over 60% of the tumor-specific CD4+ T cells in the host. Concomitantly, tumor-specific CD4+ T effector cells showed traits of chronic exhaustion as evidenced by their high expression of the PD-1, TIM-3, 2B4, TIGIT, and LAG-3 inhibitory molecules. While blockade of the PD-1/PD-L1 pathway with anti-PD-L1 antibodies or depletion of tumor-specific Treg cells alone failed to reverse tumor recurrence, combination of PD-L1 blockade with tumor-specific Treg cell depletion effectively mediated disease regression. Furthermore, blockade with a combination of anti-PD-L1 and anti-LAG-3 antibodies overcame the requirement to deplete tumor-specific Treg cells. In contrast, successful treatment of primary melanoma with adoptive cell therapy required only Treg depletion or antibody therapy, underscoring the differences in the characteristics of treatment between primary and relapsing cancer. These data highlight the need for preclinical development of combined immunotherapy approaches specifically targeting recurrent disease.

Cutting Edge: Epigenetic Regulation of Foxp3 Defines a Stable Population of CD4+ Regulatory T Cells in Tumors from Mice and Humans

“…Phenotypic characterization of intratumoral Tregs revealed a marked upregulation of Treg signature genes (CTLA-4, GITR, and Eos), a characteristic likely attributed to Tregs responding to tissue-specific and/or tumor neoantigens (Supplemental Fig. 1C) (7,14).…”

Combination of adoptive cell transfer, anti-PD-L1 and anti-LAG-3 antibodies for the treatment of recurrent tumors

“…Of note, we observed these effects regardless of the presence or absence of Tregs. 6 Our results indicated that TAA-specific CD4 + tumor recurrence may result from the exhaustion of tumor-associated antigen (tAA)-specific t cells, which often occurs upon chronic antigen stimulation. we have recently shown that the blockade of the t-cell inhibitory receptors PD-L1 and LAG-3 restores tAA-specific CD4 + t-cell functions in mice bearing recurrent neoplasms, resulting in robust antineoplastic effects.…”

“…[3][4][5] We have recently demonstrated that Treg-mediated immunosuppression and the chronic exhaustion of TAA-specific CD4 + T cells are deeply intertwined in the course of tumor recurrence. 6 Using a mouse model of melanoma combined with the adoptive transfer of CD4 + T cells and Tregs recognizing the melanoma differentiation antigen tyrosinase-related protein 1 (TYRP1), 2 we observed the accumulation of TAA-specific Tregs, the exhaustion of TAA-specific effector T cells, as well as an increase in the serum levels of the interferon γ (IFNγ)-inducible chemokines CXCL9 and CXCL10 during tumor recurrence. Programmed cell death 1 ligand 1 (PD-L1, also known as B7-H1 and CD274) blockade or Treg depletion could successfully treat primary neoplastic lesions in combination with adoptive cell transfer (ACT).…”

Th1 cells in cancer-associated inflammation

“…This phenomenon is called "T cell exhaustion". Even though CD8 + T lymphocytes have been demonstrated to act in the direct elimination of virus-infected or malignant cells, recently data started to emerge on the importance of Th1 cell functions under chronic inflammation (Goding et al, 2013;Perreau et al, 2014;Kong et al, 2015). Cytotoxic responses are facilitated and reinforced through the actions of the Th1 subset.…”