The emerging field of checkpoint receptors has revealed a latent, and powerful, ability of the adaptive immune system to shrink or eliminate tumors. Single agent response rates for checkpoint inhibitors, such as anti-PD-1 are still relatively low and preliminary results suggest that combinatorial approaches are significantly more effective. Recent studies have demonstrated that co-expression of PD-1 and the emerging checkpoint molecule Tim-3 is frequent in tumor infiltrating lymphocytes (TIL) and pre-clinical data suggest that combined targeting of PD-1 and Tim-3 produces synergistic effects on tumor regression. However, it is not clear how antibodies targeting these proteins, either in mono- or duo-therapy, modulate downstream signaling events. Resistance (or therapeutic escape) could also occur due to compensatory upregulation of an alternative checkpoint receptor after blockade of a single receptor, mediated in part by intracellular signaling cross talk. Molecular or functional cooperation between these proteins has not been examined in the context of freshly isolated TIL from human cancer patients. Intriguingly, the PI3K/Akt/mTOR signaling pathway is known to be inhibited or activated by PD-1 or Tim-3, respectively, suggesting that this signaling pathway is an important node for the regulation of T cell exhaustion. Based on emerging data, we hypothesize that PD-1 and Tim-3 cooperate to control the function of tumor-infiltrating exhausted/effector CD8+ T cells, and that modulation of PD-1 and Tim-3 signaling cross-talk modulates T cell receptor (TCR) activation in cancer. We propose to define pathways of Tim-3/PD-1 signaling and functional crosstalk in tumor-infiltrating activated vs exhausted CD8+ CTL from head and neck cancer (HNC) patients. We will then determine the extent to which Tim-3 modifies the effects of PD-1 on activated effector vs. exhausted CTL in a mouse model of HNC. Lastly, we will define pathways of compensatory ICR expression and function in response to PD-1 or Tim-3 blockade.

Public Health Relevance

The immune system is important to control tumor growth and appears to be a good target for cancer therapy. Recently FDA-approved antibodies that stimulate the immune system against cancer cells by blocking a single inhibitory signal are partially effective, but improvements are necessary. We propose to study a second inhibitory protein on immune cells, since the two inhibitory proteins may work together to suppress lymphocytes, and blocking both inhibitory proteins may provide more effective cancer treatments.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Research Project (R01)
Project #
Application #
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Pittsburgh
Schools of Medicine
United States
Zip Code
Avery, Lyndsay; Filderman, Jessica; Szymczak-Workman, Andrea L et al. (2018) Tim-3 co-stimulation promotes short-lived effector T cells, restricts memory precursors, and is dispensable for T cell exhaustion. Proc Natl Acad Sci U S A 115:2455-2460
Liu, Zhuqing; McMichael, Elizabeth L; Shayan, Gulidanna et al. (2018) Novel Effector Phenotype of Tim-3+ Regulatory T Cells Leads to Enhanced Suppressive Function in Head and Neck Cancer Patients. Clin Cancer Res 24:4529-4538
Shayan, Gulidanna; Kansy, Benjamin A; Gibson, Sandra P et al. (2018) Phase Ib Study of Immune Biomarker Modulation with Neoadjuvant Cetuximab and TLR8 Stimulation in Head and Neck Cancer to Overcome Suppressive Myeloid Signals. Clin Cancer Res 24:62-72
Shayan, Gulidanna; Srivastava, Raghvendra; Li, Jing et al. (2017) Adaptive resistance to anti-PD1 therapy by Tim-3 upregulation is mediated by the PI3K-Akt pathway in head and neck cancer. Oncoimmunology 6:e1261779
Kansy, Benjamin A; Concha-Benavente, Fernando; Srivastava, Raghvendra M et al. (2017) PD-1 Status in CD8+ T Cells Associates with Survival and Anti-PD-1 Therapeutic Outcomes in Head and Neck Cancer. Cancer Res 77:6353-6364
Concha-Benavente, Fernando; Ferris, Robert L (2017) Reversing EGFR Mediated Immunoescape by Targeted Monoclonal Antibody Therapy. Front Pharmacol 8:332
Albergotti, William G; Gooding, William E; Kubik, Mark W et al. (2017) Assessment of Surgical Learning Curves in Transoral Robotic Surgery for Squamous Cell Carcinoma of the Oropharynx. JAMA Otolaryngol Head Neck Surg 143:542-548
Jie, Hyun-Bae; Srivastava, Raghvendra M; Argiris, Athanassios et al. (2017) Increased PD-1+and TIM-3+TILs during Cetuximab Therapy Inversely Correlate with Response in Head and Neck Cancer Patients. Cancer Immunol Res 5:408-416
Mazorra, Zaima; Lavastida, Anabel; Concha-Benavente, Fernando et al. (2017) Nimotuzumab Induces NK Cell Activation, Cytotoxicity, Dendritic Cell Maturation and Expansion of EGFR-Specific T Cells in Head and Neck Cancer Patients. Front Pharmacol 8:382
Lang Kuhs, Krystle A; Kreimer, Aimée R; Trivedi, Sumita et al. (2017) Human papillomavirus 16 E6 antibodies are sensitive for human papillomavirus-driven oropharyngeal cancer and are associated with recurrence. Cancer 123:4382-4390

Showing the most recent 10 out of 16 publications