PDIA3
Overview
PDIA3 (Protein Disulfide Isomerase Family A Member 3, also known as ERp57/GRP58) is an endoplasmic reticulum chaperone that participates in the MHC class I antigen-processing and peptide-loading complex. It assists in folding of newly synthesized MHC class I heavy chains in concert with calreticulin (CALR) and tapasin (TAPBP). In cancer, somatic mutations in PDIA3 and other antigen-processing-machinery (APM) genes have been identified as candidate immune-escape mechanisms.
Alterations observed in the corpus
- PDIA3 somatic mutations detected in 1 of 2 high-TIL (TIL-rich) colorectal carcinomas in the antigen-processing-machinery (APM) gene analysis from the 619-case WES cohort (NHS/HPFS); APM mutations in aggregate were enriched in TIL-rich tumors, consistent with positive selection for immune escape under immune pressure. PMID:27149842
Cancer types (linked)
- COADREAD: PDIA3 is a component of the MHC class I peptide-loading complex (alongside CALR, TAPBP, TAP1, TAP2, CANX) found to carry somatic mutations enriched in TIL-high colorectal tumors (Figure 6C; Table S10). PMID:27149842
Co-occurrence and mutual exclusivity
- Co-occurs with somatic mutations in other APM components (B2M, CALR, CANX, HSPA5, TAP1, TAP2, TAPBP) in TIL-rich colorectal tumors as part of an adaptive immune-escape signature. PMID:27149842
Therapeutic relevance
- APM mutations including PDIA3 represent a candidate adaptive resistance mechanism to immune attack and potentially to checkpoint-inhibitor therapy; whether PDIA3-mutant tumors are less responsive to anti-PD-1/PD-L1 was explicitly left as an open question by Giannakis et al. PMID:27149842
Open questions
- Whether PDIA3 somatic mutations functionally impair MHC class I antigen presentation or merely co-occur with immune infiltration as passengers is not resolved in the current corpus.
- Whether PDIA3-mutant CRCs exhibit primary or acquired resistance to immune-checkpoint inhibitors is untested. PMID:27149842
Sources
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