T Lymphocyte-Specific Deletion of SHP1 and SHP2 Promotes Activation-Induced Cell Death of CD4+ T Cells and Impairs Antitumor Response

ABSTRACT SHP1 (PTPN6) and SHP2 (PTPN11) are closely related protein-tyrosine phosphatases (PTPs), which are autoinhibited until their SH2 domains bind paired tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory/switch motifs (ITIMs/ITSMs). These PTPs bind overlapping sets of ITIM/ITSM-bearing proteins, suggesting that they might have some redundant functions. By studying T cell-specific single and double knockout mice, we found that SHP1 and SHP2 redundantly restrain naïve T cell differentiation to effector and central memory phenotypes, with SHP1 playing the dominant role. Surprisingly, loss of SHP2 alone in T cells enhanced the antitumor effects of anti-PD-1 antibodies, whereas there was no effect of SHP1 deletion. Also unexpectedly, the absence of both PTPs resulted in poorer tumor control and failure to respond to PD-1 blockade, associated with reduced frequency and activation of T cells and dendritic cells. Mechanistic studies revealed that CD4+, but not CD8+ T cells lacking SHP1 and SHP2 show increased activation-induced cell death upon anti-CD3/CD28 stimulation. Adoptive transfer of antigen-specific CD4+ T cells restored normal levels of tumor control in mice lacking both PTPs. Together, our results demonstrate that SHP1 or SHP2 is required to prevent activation-induced cell death of CD4+ T cells and is critical for tumor immunity, raising the possibility that inhibition of SHP2 might augment the therapeutic efficacy of PD-1-based immune therapy. SIGNIFICANCE STATEMENT SHP1 and SHP2 are related protein tyrosine phosphatases that associate with several of the same ITIM/ITSM-containing receptors or T cell receptor (TCR) signaling molecules. The individual roles of SHP1 and SHP2 in T cells have been reported previously, but potentially redundant functions are less well understood. Here we uncover an essential function in CD4+ T cells that is manifest only in the absence of both enzymes and is critical for the control of tumors. Competing Interest Statement : B.G.N. is a co-founder of Northern Biologics, Limited, Navire Pharma, Lighthorse Therapeutics, and Aethon Therapeutics, from which he has received consulting fees and equity. His spouse owns equity in Moderna Inc, Revolution Medicines Inc, and during the course of this work, owned equity in Mirati Therapeutics, Regeneron, and Amgen. He serves on the Scientific Advisory Boards of Arvinas, Koijin Therapeutics, and Recursion Pharma and receives consulting fees and equity from the former two and equity from the latter. J.W. is founder and advisor for Remunix Inc., from which he has received consulting fees and equity, as well as sponsored research funds in the past 12 months. J.W. also received consulting fees from Rootpath Genomics, Bristol Myers Squibb, Regeneron, Hanmi, and LAV Fund. All other authors declare no competing interests. Footnotes Competing Interest Statement: B.G.N. is a co-founder of Northern Biologics, Limited, Navire Pharma, Lighthorse Therapeutics, and Aethon Therapeutics, from which he has received consulting fees and equity. His spouse owns equity in Moderna Inc, Revolution Medicines Inc, and during the course of this work, owned equity in Mirati Therapeutics, Regeneron, and Amgen. He serves on the Scientific Advisory Boards of Arvinas, Koijin Therapeutics, and Recursion Pharma and receives consulting fees and equity from the former two and equity from the latter. J.W. is founder and advisor for Remunix Inc., from which he has received consulting fees and equity, as well as sponsored research funds in the past 12 months. J.W. also received consulting fees from Rootpath Genomics, Bristol Myers Squibb, Regeneron, Hanmi, and LAV Fund. All other authors declare no competing interests.