Research ArticleCancer Immunology

Dual enhancement of T and NK cell function by pulsatile inhibition of SHIP1 improves antitumor immunity and survival

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Sci. Signal.  10 Oct 2017:
Vol. 10, Issue 500, eaam5353
DOI: 10.1126/scisignal.aam5353

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Finding the right balance in immunotherapy

To stimulate the immune system’s activity against tumors, therapies often inhibit the regulatory pathways that suppress or counteract stimulatory signaling in immune cells. The phosphatase SHIP1 is one such target; however, chronic inhibition or genetic ablation of SHIP1 in mouse models of cancer fails to induce effective antitumor immunity, perhaps because chronic activation causes immune cell exhaustion. Gumbleton et al. found that, instead, a pulsatile regimen of SHIP1 inhibition not only enhanced the antitumor activity of critical populations of immune cells and extended the survival of mice with lymphoma and colon cancer but also induced immunological memory against the tumor cells. This treatment strategy may thus be effective at killing various types of tumors and preventing relapse in cancer patients.

Abstract

The success of immunotherapy in some cancer patients has revealed the profound capacity for cytotoxic lymphocytes to eradicate malignancies. Various immunotherapies work by blocking key checkpoint proteins that suppress immune cell activity. The phosphatase SHIP1 (SH2-containing inositol polyphosphate 5-phosphatase) limits signaling from receptors that activate natural killer (NK) cells and T cells. However, unexpectedly, genetic ablation studies have shown that the effector functions of SHIP1-deficient NK and T cells are compromised in vivo. Because chronic activation of immune cells renders them less responsive to activating signals (a host mechanism to avoid autoimmunity), we hypothesized that the failure of SHIP1 inhibition to induce antitumor immunity in those studies was caused by the permanence of genetic ablation. Accordingly, we found that reversible and pulsatile inhibition of SHIP1 with 3-α-aminocholestane (3AC; “SHIPi”) increased the antitumor response of NK and CD8+ T cells in vitro and in vivo. Transient SHIP1 inhibition in mouse models of lymphoma and colon cancer improved the median and long-term tumor-free survival rates. Adoptive transfer assays showed evidence of immunological memory to the tumor in hematolymphoid cells from SHIPi-treated, long-term surviving mice. The findings suggest that a pulsatile regimen of SHIP1 inhibition might be an effective immunotherapy in some cancer patients.

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