The human leukocyte antigen as a candidate tumor suppressor

Here we argue in support of the human leukocyte antigen (HLA) supergene as a tumor suppressor. HLA is recurring mutational target large and diverse group malignancies. The suppressor function linked to an embryonic/stemness drug resistance phenotype. A deeper understanding distinct roles HLA, including immunosurveillance, stemness, functions, could illuminate limited responses cancer patients. Furthermore, it would provide guidelines for design new therapeutic strategies, potential modulating expression stem cell compartment. highly polymorphic encoding major histocompatibility complex (MHC) proteins humans. defined neighboring genes on chromosome, which are inherited together due genetic linkage usually functionally related. maps chromosome 6p21 and, besides MHC proteins, encodes molecules whose main facilitate presentation relevant immune cells, such transporter associated with processing (TAP) subunits TAP1 TAP2, necrosis factor (TNF), natural killer (NK) ligands MICA MICB. present cytosolic peptides that promote cytotoxic killing cells expressing aberrant antigens, whether extrinsic, infectious pathogens, or intrinsic, those derived from cancer-associated somatic mutations. was first explored through studies allogeneic transplantation. Tyzzer Little noticed early 20th century determinants susceptibility transplantation mice does not conform Mendelian genetics, ultimately reaching conclusion many loci involved. As role antigens graft rejection became clearer, researchers grew intrigued by controversial topic how semi-allogeneic embryos successfully implant develop immunocompetent mother. In 1988, Desoye colleagues took advantage then-emergent vitro fertilization technology directly measure pre-implantation embryos. Indirect immunofluorescence revealed lack class I, II, β2-microglobulin (B2M), component I molecule required stability surface complex, blastomeres, leading authors postulate downregulation prevents implanting embryo despite its complement paternal (Desoye et al., 1988Desoye G. Dohr G.A. Motter W. Winter R. Urdl Pusch H. Uchanska-Ziegler B. Ziegler A. Lack II preimplantation embryos.J. Immunol. 1988; 140: 4157-4159PubMed Google Scholar). Class molecules, today believed be expressed effectively all nucleated fact embryonic (hESCs). Additional work genetics demonstrated order malignancy host, tolerance escape mechanisms need invoked, neo-antigens generated within perceived non-self even syngeneic host. Given played presentation, several groups started examine document HLA-I B2M variety models. resurgence interest this came growing promise hESC lines their directed differentiation resources tissue engineering therapy. thought potentially bypass concerns about rejection, vastly broadening applicability approach. However, were also found re-express MHC-I upon differentiation, consistent what happens normal development, well response interferon- γ (IFN-γ) treatment, making them targets after all. Theodore Boveri’s landmark monograph “Concerning Origin Malignant Tumors,” published Germany 1914, postulated nuclear induce stop dividing environmental cues, these impaired malignancies secondary “nuclear defects,” unrestrained proliferation no longer responds external signals. Years later, 1969, Harris recessive nature wide types showing fusion non-transformed suppress malignant Knudson then his two-hit hypothesis based mathematical modeling sporadic familiar retinoblastoma; retinoblastoma (RB1) gene prove cloned. productive decade identification key cancer-causing ensued, focusing tracing defects behind numerous syndromes, Li-Fraumeni syndrome familial breast cancer. Interestingly, majority syndromes arise loss-of-function mutations, often areas affected loss heterozygosity (LOH). Tumor genes, therefore, leads development cancer, correlate severity progression disease, restoration can quell suppressors mutated, contained regions heterozygosity, otherwise repressed comprehensive study 1990s evaluated paired primary metastatic tumors, breast, colon, urinary bladder, kidney carcinomas, suggesting relationship between disease (Cordon-Cardo 1991Cordon-Cardo C. Fuks Z. Drobnjak M. Moreno Eisenbach L. Feldman Expression HLA-A,B,C populations carcinomas.Cancer Res. 1991; 51: 6372-6380PubMed Most lesions displayed HLA-positive phenotype, especially patients without while minority HLA-negative documented disease. Conversely, most phenotype mixed Evaluation causes has been hampered locus, alignment reference genome inadequate. Even so, foundational cataloguing landscape point mutations tumors identified alterations HLA-A head neck cancers, lung squamous colorectal carcinomas (Lawrence 2014Lawrence M.S. Stojanov P. Mermel C.H. Robinson J.T. Garraway L.A. Golub T.R. Meyerson Gabriel S.B. Lander E.S. Getz Discovery saturation analysis across 21 tumour types.Nature. 2014; 505: 495-501Crossref PubMed Scopus (1930) Shukla developed computational pipeline allowed inference germline alleles HLA-A, HLA-B, HLA-C relatively low-coverage whole-exome sequencing (WES) data, used assess 7,930 pairs healthy tissues (Shukla 2015Shukla S.A. Rooney Rajasagi Tiao Dixon P.M. Lawrence Stevens J. Lane W.J. Dellagatta J.L. Steelman S. al.Comprehensive genes.Nat. Biotechnol. 2015; 33: 1152-1158Crossref (324) This 298 non-silent, overwhelmingly multitude Subsequent expansions algorithms evaluation LOH 100 TRACERx non-small (NSCLC) patients, yielding rate 40% high subclonal neoantigen burden enriched at sites (McGranahan 2017McGranahan N. Rosenthal Hiley C.T. Rowan A.J. Watkins T.B.K. Wilson Birkbak N.J. Veeriah Van Loo Herrero al.Allele-specific evolution.Cell. 2017; 171: 1259-1271Abstract Full Text PDF (500) More recently, approach extended over 83,000 patient samples spanning 59 different solid types, overall 17% (range 2%–42%) (Montesion 2020Montesion Murugesan K. Jin D.X. Sharaf Sanchez Guria Minker Li Fisher V. Sokol al.Somatic widespread mechanism evasion refines use biomarker checkpoint inhibitor response.Cancer Discov. 2020; 11: 282-292Crossref (31) While phased long-read technologies will adequately characterize nonetheless pervasive LOH, historically shown (Figure 1A). (and MHC-II) targeted degradation specific membrane-associated RING-CH (MARCH) ubiquitin ligases, structural homologs viral E3 ligase K3 K5 Kaposi’s sarcoma-associated herpesvirus. Mechanistic have uncovered interfering function. For example, HPV-related E5 E7 implicated preventing repressing transcription respectively; HPV binds invariant chain MHC-II Golgi ER, trafficking It erroneous think suppressive effects entirely mediated impact immunosurveillance. Both vivo experiments suggest possess stem-like properties. subpopulation exposure Docetaxel hormone-refractory prostate exhibited multiple markers concomitant increase signaling pathways, namely Notch Hedgehog (Domingo-Domenech 2012Domingo-Domenech Vidal S.J. Rodriguez-Bravo Castillo-Martin Quinn Rodriguez-Barrueco Bonal D.M. Charytonowicz E. Gladoun de la Iglesia-Vicente al.Suppression acquired docetaxel depletion notch- hedgehog-dependent tumor-initiating cells.Cancer Cell. 2012; 22: 373-388Abstract (312) small fraction showed HLA- cytokeratin (CK18/19)-negative increased treatment. Quantification statistically significant survival difference, correlation Gleason score likelihood disseminated isolate demonstrating initiating capacity sarcoma (Han 2017Han D. Demicco Domingo-Domenech Maki R.G. Cordon-Cardo Targeting therapy.Stem Cell (Amst.). 21: 117-123Crossref (6) Cells sorted into HLA-I-positive -negative fractions, few 10 negative being able form spheres. Induction all-trans retinoic acid led reduced formation. contextualize findings, helpful consider epigenetic regulation expression. genome-wide CRISPR/Cas9 screen polycomb repressive 2 (PRC2) transcriptional silencing pathway, bivalent chromatin signature low cancers mimics developmental process (Burr 2019Burr M.L. Sparbier C.E. Chan K.L. Y.C. Kersbergen Lam E.Y.N. Azidis-Yates Vassiliadis Bell C.C. Gilan O. al.An evolutionarily conserved silences pathway enables cancer.Cancer 2019; 36: 385-401Abstract (165) Of note, pharmacological inhibition EED EZH1/2 anti-tumor immunity restoring At same time, homeobox DUX4, regulator during cleavage stages embryogenesis, aberrantly lead decreased anti-CTLA-4 treatment failure triggering network (Chew 2019Chew G.L. Campbell A.E. De Neef Sutliff N.A. Shadle S.C. Tapscott Bradley R.K. DUX4 suppresses blockade.Dev. 50: 658-671Abstract (34) Taken together, developmentally regulated via critical regulatory networks active earliest development. 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