Cell Stress Response in
Tumor microenvironments drive cell stress that hinders anti-tumor immunity. We study the stress response in T cells in tumors (TILs). We have found that activation of the stress response in TILs impairs T cell anti-tumor immunity. We have dissected the stress response pathways in order to discover novel molecular targets to repair T cell function in tumors. We find that targeting aspects of the stress response is able to repair metabolic, translational, and oxidative stress-based (ref) inhibition of T cell function in tumors.
Figure 5. Inhibition of PERK axis augments T cell-specific tumor control. Individual graphs of mice bearing 7-day B16F1-OVA tumors left untreated (n=5) or treated intravenously with 5x105 7-day expanded OT-1+ (Teff) (n=8) or PERK KO (n=7) T cells. Tumor size recorded every other day for 3 weeks. Lines represent individual mice. (B) Survival to 45 days or tumor size of 400mm2 was recorded, Log-rank test, **p<0.01 survival proportions of mice treated with Teff (12%) versus PERK KO T cells (86%) (C) Mice bearing 7-day B16F10 melanomas were treated intravenously with 2x106 7-day expanded Pmel (Teff) or Pmel T cells developed in the presence of (B) PERK inhibitor (PERK I T) or (C) ERO1a inhibitor (ERO1a I T). Tumor size recorded every other day for 3 weeks. Lines represent individual mice. Linear regression of Teff versus PERK KO or inhibitor-treated T cell groups, n=5-6 mice per group, ****p<0.0001. Experiments repeated twice.
Figure 7. PERK inhibition reduces CD8+ TIL mtROS and augments anti-PD-1 therapy. (A) Representative FACS plot and quantification of mtROS/PD-1+ CD8+ T cells from PBMC and tumor of three patients with pleomorphic undifferentiated high grade deep (PU HGD) sarcoma. Gates are set from isotype controls. PERK inhibitor (PERK I) or vehicle control was administered for 1 week (days 7-14) to mice bearing MCA-205-OVA sarcomas. (B) Representative FACS plots and quantification of mtROS/PD-1 TILs gated from CD45[A1] +/ CD8+ populations. Gates are set from isotype control data. (C) Absolute number of CD45+/PI-/ CD8[A2] + TILs calculated per gram of tumor weight. Bar graphs represent 4-5 mice per group and are shown as SEM. Individual experiments repeated twice. Students t test, *p<0.05, ***p<0.001. PERK I or vehicle control was administered beginning after 7 days of tumor growth to mice bearing MCA-205-OVA sarcomas and anti-PD-1 or isotype antibody was administered on day 12 and every four days thereafter. Anti-CD8 was administered every 2-3 days beginning 5 days after tumor inoculation. (D) Composite and (E) individual graphs of tumor growth measured every other day for 40 days with complete response (CR) listed per group, composite data represented as SEM. Linear regression of combination measured against anti-PD-1 therapy, ****p<0.0001. (F) Survival to 41 days or tumor size of 200mm2 was recorded, Log-rank test, **p<0.01 survival proportions of anti-PD-1 therapy (28%) versus combination therapy (100%). Combination experiment repeated twice, anti-CD8 depletion condition performed once.