PMID- 34940799
OWN - NLM
STAT- MEDLINE
DCOM- 20220401
LR  - 20230302
IS  - 2374-2445 (Electronic)
IS  - 2374-2437 (Print)
IS  - 2374-2437 (Linking)
VI  - 8
IP  - 3
DP  - 2022 Mar 1
TI  - Human Leukocyte Antigen Class I Antigen-Processing Machinery Upregulation by 
      Anticancer Therapies in the Era of Checkpoint Inhibitors: A Review.
PG  - 462-473
LID - 10.1001/jamaoncol.2021.5970 [doi]
AB  - IMPORTANCE: Although typically impressive, objective responses to immune 
      checkpoint inhibitors (ICIs) occur in only 12.5% of patients with advanced 
      cancer. The majority of patients do not respond due to cell-intrinsic resistance 
      mechanisms, including human leukocyte antigen (HLA) class I antigen-processing 
      machinery (APM) defects. The APM defects, which have a negative effect on 
      neoantigen presentation to cytotoxic T lymphocytes (CTLs), are present in the 
      majority of malignant tumors. These defects are caused by gene variations in less 
      than 25% of cases and by dysregulated signaling and/or epigenetic changes in most 
      of the remaining cases, making them frequently correctable. This narrative review 
      summarizes the growing clinical evidence that chemotherapy, targeted therapies, 
      and, to a lesser extent, radiotherapy can correct HLA class I APM defects in 
      cancer cells and improve responses to ICIs. OBSERVATIONS: Most chemotherapeutics 
      enhance HLA class I APM component expression and function in cancer cells, tumor 
      CTL infiltration, and responses to ICIs in preclinical and clinical models. 
      Despite preclinical evidence, radiotherapy does not appear to upregulate HLA 
      class I expression in patients and does not enhance the efficacy of ICIs in 
      clinical settings. The latter findings underscore the need to optimize the dose 
      and schedule of radiation and timing of ICI administration to maximize their 
      immunogenic synergy. By increasing DNA and chromatin accessibility, epigenetic 
      agents (histone deacetylase inhibitors, DNA methyltransferase inhibitors, and 
      EZH2 inhibitors) enhance HLA class I APM component expression and function in 
      many cancer types, a crucial contributor to their synergy with ICIs in patients. 
      Furthermore, epidermal growth factor receptor (EGFR) inhibitors and 
      BRAF/mitogen-activated protein kinase kinase inhibitors are effective at 
      upregulating HLA class I expression in EGFR- and BRAF-variant tumors, 
      respectively; these changes may contribute to the clinical responses induced by 
      these inhibitors in combination with ICIs. CONCLUSIONS AND RELEVANCE: This 
      narrative review summarizes evidence indicating that chemotherapy and targeted 
      therapies are effective at enhancing HLA class I APM component expression and 
      function in cancer cells. The resulting increased immunogenicity and recognition 
      and elimination of cancer cells by cognate CTLs contributes to the antitumor 
      activity of these therapies as well as to their synergy with ICIs.
FAU - Sadagopan, Ananthan
AU  - Sadagopan A
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston.
FAU - Michelakos, Theodoros
AU  - Michelakos T
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston.
FAU - Boyiadzis, Gabriella
AU  - Boyiadzis G
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston.
FAU - Ferrone, Cristina
AU  - Ferrone C
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston.
FAU - Ferrone, Soldano
AU  - Ferrone S
AD  - Department of Surgery, Massachusetts General Hospital, Harvard Medical School, 
      Boston.
LA  - eng
GR  - R01 CA230275/CA/NCI NIH HHS/United States
GR  - R01 DE028172/DE/NIDCR NIH HHS/United States
GR  - R03 CA219603/CA/NCI NIH HHS/United States
GR  - R03 CA253319/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, U.S. Gov't, Non-P.H.S.
PT  - Review
PL  - United States
TA  - JAMA Oncol
JT  - JAMA oncology
JID - 101652861
RN  - 0 (HLA Antigens)
RN  - 0 (Histocompatibility Antigens Class I)
RN  - 0 (Immune Checkpoint Inhibitors)
SB  - IM
MH  - HLA Antigens
MH  - *Histocompatibility Antigens Class I/genetics/metabolism
MH  - Humans
MH  - *Immune Checkpoint Inhibitors/therapeutic use
MH  - *Neoplasms/drug therapy/genetics
MH  - T-Lymphocytes, Cytotoxic
MH  - Up-Regulation
PMC - PMC8930447
MID - NIHMS1770590
COIS- Conflicts of Interest: The authors declare no potential conflicts of interest.
EDAT- 2021/12/24 06:00
MHDA- 2022/04/02 06:00
PMCR- 2023/03/01
CRDT- 2021/12/23 12:48
PHST- 2021/12/24 06:00 [pubmed]
PHST- 2022/04/02 06:00 [medline]
PHST- 2021/12/23 12:48 [entrez]
PHST- 2023/03/01 00:00 [pmc-release]
AID - 2787232 [pii]
AID - 10.1001/jamaoncol.2021.5970 [doi]
PST - ppublish
SO  - JAMA Oncol. 2022 Mar 1;8(3):462-473. doi: 10.1001/jamaoncol.2021.5970.