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.