Person:

Anderson, Ana

The remarkable clinical success of cancer immunotherapies targeting the checkpoint receptors CTLA-4 and PD-1 has generated considerable excitement and emboldened efforts to build on this important foundation. Research efforts are now focused on understanding the mechanism of action of these immunotherapies, identifying new inhibitory mechanisms that could be targeted to achieve responses in patients with refractory cancers, and developing approaches that might exhibit efficacy against “immunologically inert” tumors. The outstanding challenges in moving forward are developing reliable strategies for determining which patients will respond optimally to a given immunotherapy, and what combination of immunotherapies and conventional therapies will prove beneficial against each tumor type. These issues were discussed in a one-day workshop at the SITC meeting in November 2014.

While T cell immunity initially limits Mycobacterium tuberculosis infection, why T cell immunity fails to sterilize the infection and allows recrudescence is not clear. One hypothesis is that T cell exhaustion impairs immunity and is detrimental to the outcome of M. tuberculosis infection. Here we provide functional evidence for the development T cell exhaustion during chronic TB. Second, we evaluate the role of the inhibitory receptor T cell immunoglobulin and mucin domain–containing-3 (TIM3) during chronic M. tuberculosis infection. We find that TIM3 expressing T cells accumulate during chronic infection, co-express other inhibitory receptors including PD1, produce less IL-2 and TNF but more IL-10, and are functionally exhausted. Finally, we show that TIM3 blockade restores T cell function and improves bacterial control, particularly in chronically infected susceptible mice. These data show that T cell immunity is suboptimal during chronic M. tuberculosis infection due to T cell exhaustion. Moreover, in chronically infected mice, treatment with anti-TIM3 mAb is an effective therapeutic strategy against tuberculosis.

Co-inhibitory and checkpoint molecules suppress T-cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. While immune checkpoint blockade (ICB) has emerged as a successful treatment option for multiple human cancers, severe autoimmune-like side effects limit its application. Here we found the gene encoding the Peptidoglycan Recognition Protein 1 (PGLYRP1) to be highly co-expressed with co-inhibitory molecules and hypothesized that it might be a promising target for cancer immunotherapy. Indeed, genetic deletion of PGLYRP1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8+ T cells, suggesting an inhibitory function of PGLYRP1 in CD8+ T cells. Surprisingly, the genetic deletion of PGLYRP1 strongly protected against the development of experimental autoimmune encephalomyelitis (EAE), a model of autoimmune disease in the central nervous system (CNS). Pglyrp1-deficient myeloid cells had a defect in antigen presentation and T-cell activation, indicating that PGLYRP1 might act as a proinflammatory molecule in myeloid cells during autoimmunity. Our results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.