Qa-1(b) modulates resistance to anti–PD-1 immune checkpoint blockade in tumors with defects in antigen processing Journal Article
| Authors: | Zhang, X.; Sabio, E.; Krishna, C.; Ma, X.; Wang, J.; Jiang, H.; Havel, J. J.; Chan, T. A. |
| Article Title: | Qa-1(b) modulates resistance to anti–PD-1 immune checkpoint blockade in tumors with defects in antigen processing |
| Abstract: | Immune checkpoint blockade (ICB) has improved cancer care, but ICB is only effective in some patients. The molecular mechanisms that influence ICB therapy response are not completely understood. The non-classical MHC class I molecule HLA-E and its mouse ortholog, Qa-1b, present a limited set of peptides in a TAP1-dependent manner to the NKG2A/CD94 heterodimer to transduce an inhibitory signal to natural killer (NK) and CD8þ T cells. However, deficiency of TAP1 allows Qa-1b to present an alternative peptidome to Qa-1b–restricted T-cell receptors of cytotoxic T cells. In this study, we used CRISPR–Cas9 to study the relationship between TAP1, Qa-1b, and response to anti-PD1 therapy. We hypothesized that immunotherapy response in TAP1-deficient tumors would be influenced by Qa-1b. Strikingly, using a syngeneic orthotopic mouse model, we found that although TAP1-deficient tumors were resistant to anti-PD1 treatment, antiPD1 response was significantly enhanced in tumors lacking both TAP1 and Qa-1b. This increased sensitivity is partially dependent on NK cells. TAP1-deficient tumors were associated with an increase of intratumoral regulatory T cells (Treg) and neutrophils, whereas tumors lacking both TAP1 and Qa-1b exhibited an increased CD8þ T-cell to Treg ratio. These data suggest that direct inhibition of Qa-1b may alter the immune microenvironment to reverse resistance to anti-PD1 therapy, particularly in the context of antigen-processing defects. Implications: This study reveals important functional crosstalk between classical TAP-dependent MHC complexes and Qa-1b/ HLA-E, particularly in tumors with impaired antigen-processing machinery. This can dramatically influence immunotherapy efficacy. 2021 American Association for Cancer Research. |
| Journal Title: | Molecular Cancer Research |
| Volume: | 19 |
| Issue: | 6 |
| ISSN: | 1541-7786 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-06-01 |
| Start Page: | 1076 |
| End Page: | 1084 |
| Language: | English |
| DOI: | 10.1158/1541-7786.Mcr-20-0652 |
| PUBMED: | 33674442 |
| PROVIDER: | scopus |
| PMCID: | PMC8178214 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 July 2021 -- Source: Scopus |
Altmetric
Citation Impact
BMJ Impact Analytics
Related MSK Work