Individual HLA heterogeneity and its implications for cellular immune evasion in cancer and beyond

Pagliuca, Simona; Gurnari, Carmelo; Rubio, Marie Thérèse; Visconte, Valeria; Lenz, Tobias

doi:10.3389/fimmu.2022.944872

Cited by 34 publications

(30 citation statements)

References 108 publications

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“…In sum, our study unravels the immune escape nature of post-transplant relapse in a signi cant proportion of patients and provides insights concerning the role in such a setting of the germline and somatic dysfunction of HLA heterogeneity. 33 In particular, we demonstrate that germline-determined class II HLA divergence and somatic class II HLA mutations, indels or losses can enable an environment of GvL resistance, immune evasion and unfavorable outcomes. Future studies exploring larger cohorts of patients are warranted to better establish how germline and somatic HLA dysfunction may inform daily clinical practice.…”

Section: Discussionmentioning

confidence: 81%

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

Pagliuca

Gurnari

Hercus

et al. 2023

Preprint

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Graft-versus-leukemia (GvL) reactions are responsible for the effectiveness of allogeneic hematopoietic cell transplantation as a treatment modality for myeloid neoplasia, whereby donor T- effector cells recognize leukemia neoantigens. However, a substantial fraction of patients experience relapses because of the failure of the immunological responses to control leukemic outgrowth. Here, through a broad immunogenetic study, we demonstrate that germline and somatic reduction of human leucocyte antigen (HLA) heterogeneity enhances the risk of leukemic recurrence. We show that preexistent germline-encoded low evolutionary divergence of class II HLA genotypes constitutes an independent factor associated with disease relapse and that acquisition of clonal somatic defects in HLA alleles may lead to escape from GvL control. Both class I and II HLA genes are targeted by somatic mutations as clonal selection factors potentially impairing cellular immune reactions and response to immunomodulatory strategies. These findings define key molecular modes of post-transplant leukemia escape contributing to relapse.

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Section: Discussionmentioning

confidence: 81%

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

Pagliuca

Gurnari

Hercus

et al. 2023

Preprint

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“…For instance, cytokine signaling, cancer pathways, and angiogenic signaling may restrict tumor immunity. [48][49][50] Conversely, the significant reduction in HLA-DPA1 homozygosity-which has been previously associated with dampened antigen presentation and checkpoint blockade efficacy 51 -and associated increases in computationally inferred adaptive immune subpopulations (i.e., NK and CD8 + T cells) in YOPC suggest a less immunosuppressive and more immunostimulatory microenvironment. Altogether, these findings underscore the need for deeper investigation and functional characterization of cell-autonomous and non-autonomous immunologic repercussions in YOPC tumors.…”

Section: Discussionmentioning

confidence: 94%

Multi-omic characterization reveals a distinct molecular landscape in young-onset pancreatic cancer

Ogobuiro

Baca

Ribeiro

et al. 2023

Preprint

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Purpose: Using a real-world database with matched genomic-transcriptomic molecular data, we sought to characterize the distinct molecular correlates underlying clinical differences between young-onset pancreatic cancer (YOPC; <50-yrs.) and average-onset pancreatic cancer (AOPC; ≥70-yrs.) patients. Methods: We analyzed matched whole-transcriptome and DNA sequencing data from 2430 patient samples (YOPC, n=292; AOPC, n=2138) from the Caris Life Sciences database (Phoenix, AZ). Immune deconvolution was performed using the quanTIseq pipeline. Overall survival (OS) data was obtained from insurance claims (n=4928); Kaplan-Meier estimates were calculated for age- and molecularly-defined cohorts. Significance was determined as FDR-corrected P-values (Q)<0.05. Results: YOPC patients had higher proportions of mismatch repair-deficient (dMMR)/microsatellite instability-high (MSI-H),BRCA2-mutant, andPALB2-mutant tumors compared with AOPC patients, but fewerSMAD4-,RNF43-,CDKN2A-, andSF3B1-mutant tumors. Notably, YOPC patients demonstrated significantly lower incidence ofKRASmutations compared with AOPC patients (81.3% vs. 90.9%; Q=0.004). In theKRAS-wildtype subset (n=227), YOPC tumors demonstrated fewerTP53mutations and were more likely driven byNRG1andMETfusions, whileBRAFfusions were exclusively observed in AOPC patients. Immune deconvolution revealed significant enrichment of natural killer (NK) cells, CD8+ T cells, monocytes, and M2 macrophages in YOPC patients relative to AOPC patients, which corresponded with lower rates of HLA-DPA1 homozygosity. There was an association with improved OS in YOPC patients compared with AOPC patients with KRAS-wildtype tumors (median 16.2 [YOPC-KRASWT] vs. 10.6 [AOPC-KRASWT] months; P=0.008) but notKRAS-mutant tumors (P=0.084). Conclusion: In this large, real-world multi-omic characterization of age-stratified molecular differences in PDAC, YOPC is associated with a distinct molecular landscape that has prognostic and therapeutic implications.

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“…These alterations can affect various genes, including TAP1, TAP2, LMP2, LMP7, and tapasin, as well as the 2-microglobulin locus located at 15q21. One of the most frequent causes of HLA haplotype loss in human tumors is chromosomal loss [ 61 , 62 ].…”

Section: Immune Evasion Through Hla Loss Of Heterozygositymentioning

confidence: 99%

Assessment of Impact of Human Leukocyte Antigen-Type and Cytokine-Type Responses on Outcomes after Targeted Therapy Currently Used to Treat Chronic Lymphocytic Leukemia

Andreescu

Berbec

Tănase

2023

JCM

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Tumor growth and metastasis are reliant on intricate interactions between the host immune system and various counter-regulatory immune escape mechanisms employed by the tumor. Tumors can resist immune surveillance by modifying the expression of human leukocyte antigen (HLA) molecules, which results in the impaired presentation of tumor-associated antigens, subsequently evading detection and destruction by the immune system. The management of chronic lymphocytic leukemia (CLL) is based on symptom severity and includes various types of targeted therapies, including rituximab, obinutuzumab, ibrutinib, acalabrutinib, zanubrutinib, idelalisib, and venetoclax. These therapies rely on the recognition of specific peptides presented by HLAs on the surface of tumor cells by T cells, leading to an immune response. HLA class I molecules are found in most human cell types and interact with T-cell receptors (TCRs) to activate T cells, which play a vital role in inducing adaptive immune responses. However, tumor cells may evade T-cell attack by downregulating HLA expression, limiting the efficacy of HLA-dependent immunotherapy. The prognosis of CLL largely depends on the presence or absence of genetic abnormalities, such as del(17p), TP53 point mutations, and IGHV somatic hypermutation status. These oral targeted therapies alone or in combination with anti-CD20 antibodies have replaced chemoimmunotherapy as the primary treatment for CLL. In this review, we summarize the current clinical evidence on the impact of HLA- and cytokine-type responses on outcomes after targeted therapies currently used to treat CLL.

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Individual HLA heterogeneity and its implications for cellular immune evasion in cancer and beyond

Cited by 34 publications

References 108 publications

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

Leukemia relapse via genetic immune escape after allogeneic hematopoietic cell transplantation

Multi-omic characterization reveals a distinct molecular landscape in young-onset pancreatic cancer

Assessment of Impact of Human Leukocyte Antigen-Type and Cytokine-Type Responses on Outcomes after Targeted Therapy Currently Used to Treat Chronic Lymphocytic Leukemia

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