Tumor-specific CD4+ Melanoma Tumor-infiltrating Lymphocytes

Friedman, Kevin M.; Prieto, Peter A.; Devillier, Laura; Gross, Colin; Yang, James Chih‐Hsin; Wunderlich, John R.; Rosenberg, Steven A.; Dudley, Mark E.

doi:10.1097/cji.0b013e31825898c5

Cited by 93 publications

(83 citation statements)

References 43 publications

(51 reference statements)

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“…D393-CD20 [33][34][35][36][37][38][39][40][41] (SP) specific T cell recognition after D393-CD20 SP or D393-CD20 LP vaccination was assessed ex vivo on sorted CD8 T cells (b). D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] (LP) specific T cell recognition after D393-CD20 SP or D393-CD20 LP vaccination was assessed ex vivo on CD8 T cells depleted splenocytes in an IFN-g ELISPOT (c). Five mice per group were used in each experiment.…”

Section: Discussionmentioning

confidence: 99%

“…Briefly, these mice are H-2 Class I and IA Class II knockout, and their CD8 T and CD4 T cells are restricted by the sole HLA-A*0201 and HLA-DR1*0101 molecules, respectively. 11,15 For D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] (20mer) and D393-CD20 33-41 (9mer) immunization, mice were injected twice with 100 lg of D393-CD20 20mer or 50 mg of D393-CD20 9mer were emulsified in incomplete Freund adjuvant (IFA, Sigma-Aldrich). All peptide vaccinations were done subcutaneously at the base of the tail at Days 1 and 14.…”

Section: Mouse and Vaccinationsmentioning

confidence: 99%

“…2c). To further investigate the promiscuous HLA-DR binding capacity of D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] peptide and the degeneracy of T cell recognition, the reactivity of the CD4 T cell clones was evaluated against various HLA-DR-positive and D393-CD20-negative loaded with the D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] peptide. CD4 T cell clones from patient P#1 (HLA-DRB1*04 homozygote) and patient P#7 (HLA-DRB1*04 and -DRB1*11) were reactive against the HLA-DRB1*04 positive cell line FaDu loaded with the cognate peptide (Fig.…”

Section: Characterization Of Hla-dr Restricted D393-cd20 Specific Cd4mentioning

confidence: 99%

“…The three first amino-acids used to name these peptides are indicated in boldface. T cell lines were obtained from healthy donors' PBMCs after two rounds of in vitro stimulation in microplates with 10 lg/mL of D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] peptide. Specific responses were assessed by CD4 and IFN-g staining.…”

Section: Tumor Immunologymentioning

confidence: 99%

“…24 We then evaluated the capacity of the D393-CD20 28-47 long peptide (LP) to prime HLA-A2-restricetd CTL response. To this end, mice were immunized either with the D393-CD20 [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46][47] LP or with the HLA-A2-restricted D393-CD20 derived short peptide D393-CD20 [33][34][35][36][37][38][39][40][41] (SP). As shown in Figure 5b, higher IFN-g producing specific-CTL were detected ex vivo after immunization with the D393-CD20 28-47 LP than with the SP.…”

Section: Tumor Immunologymentioning

confidence: 99%

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CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes

Vauchy

Gamonet

Ferrand

et al. 2014

Intl Journal of Cancer

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Cancer-specific splice variants gain significant interest as they generate neo-antigens that could be targeted by immune cells. CD20, a membrane antigen broadly expressed in mature B cells and in B cell lymphomas, is subject to an alternative splicing named D393-CD20 leading to loss of membrane expression of the spliced isoform. D393-CD20 expression is detectable in transformed B cells and upregulated in various lymphoma B cells. In this study, we show that D393-CD20 is translated in malignant B cells and that D393-CD20 specific CD4 T cells producing IFN-c are present in B-cell lymphoma patients. Then, we have investigated whether the 20mer D393-CD20 peptide spanning the splicing site might be targeted by the immune system and we have shown that D393-CD20-specific CD4 Th1 clones could directly recognize malignant B cell lines and kill autologous lymphoma B cells indicating that D393-CD20-derived epitopes are naturally processed and presented on tumor cells. Finally, D393-CD20 peptide-based vaccination induced specific CD8 and CD4 T cell responses in HLA-humanized transgenic mice suggesting the presentation of D393-CD20 derived peptides on both HLA Class-I and -II. These findings support further investigations on the potential use of D393-CD20 directed specific immunotherapy in B cell malignancies.The effective discovery of clinically relevant tumor antigens holds a fundamental role for the development of new diagnostic tools and anticancer immunotherapies. Generally, tumor antigens are classified as unique antigens derived from point mutations or as shared antigens. The shared antigens are further divided into tumor-specific antigens, differentiation antigens and overexpressed antigens. The prioritization of cancer antigens is based on criteria such as immunogenicity, specificity, oncogenicity. 1 One mechanism that would lead to such priority targets could be alternative splicing. Alternative splicing can change the structure of mRNA by inclusion or skipping of exons, and this may alter the function, stability or binding properties of the encoded protein. 2 Aside from its role in physiological cell adaptation, alternative splicing has been shown to occur in human diseases, including cancer. 3 Particularly, the splice variants differ between cancer and normal corresponding tissues. 4,5 Cancerspecific splice variants are thus of significant interest as they may be involved in pathogenesis and may further potentially be used as biomarkers and generate novel targets for therapy. Because immune recognition of antigenic epitopes is highly specific, alternative exon splicing could provide the structural basis for expression of novel amino-acid sequences not subject to self repertoire tolerance.We previously identified an alternative transcript of the B cell lineage membrane receptor CD20. This alternative transcript lacks 168 nucleotides within Exon 3 to 7 compared to the wild-type CD20 transcript and referred thereafter as D393-CD20. 6 D393-CD20 translation gives rise to a protein lacking the extracellular domain and ...

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Section: Discussionmentioning

confidence: 99%

Section: Mouse and Vaccinationsmentioning

confidence: 99%

Section: Characterization Of Hla-dr Restricted D393-cd20 Specific Cd4mentioning

confidence: 99%

Section: Tumor Immunologymentioning

confidence: 99%

Section: Tumor Immunologymentioning

confidence: 99%

See 3 more Smart Citations

CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes

Vauchy

Gamonet

Ferrand

et al. 2014

Intl Journal of Cancer

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Systematic analysis of CD39, CD103, CD137, and PD‐1 as biomarkers for naturally occurring tumor antigen‐specific TILs

et al. 2021

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The detection of tumor-specific T cells in solid tumors is integral to interrogate endogenous antitumor responses and to advance downstream therapeutic applications. Multiple biomarkers are reported to identify endogenous tumor-specific tumor-infiltrating lymphocytes (TILs), namely CD137, PD-1, CD103, and CD39; however, a direct comparison of these molecules has yet to be performed. We evaluated these biomarkers in primary human ovarian tumor samples using single-cell mass cytometry to compare their relative phenotypic profiles, and examined their response to autologous tumor cells ex vivo. PD-1 + , CD103 + , and CD39 + TILs all contain a CD137 + cell subset, while CD137 + TILs highly co-express the aforementioned markers. CD137 + TILs exhibit the highest expression of cytotoxic effector molecules compared to PD-1 + , CD103 + , or CD39 + TILs. Removal of CD137 + cells from PD-1 + , CD103 + , or CD39 + TILs diminish their IFN-γ secretion in response to autologous tumor cell stimulation, while CD137 + TILs maintain high HLAdependent IFN-γ secretion. CD137 + TILs exhibited an exhausted phenotype but with CD28 co-expression, suggesting possible receptiveness to reinvigoration via immune checkpoint blockade. Together, our findings demonstrate that the antitumor abilities of PD-1 + , CD103 + , and CD39 + TILs are mainly derived from a subset of CD137-expressing TILs, implicating CD137 as a more selective biomarker for naturally occurring tumor-specific TILs.

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Augmenting the Skin Immune System

Nasir

Gaspari

2012

Nanotechnology in Dermatology

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Tumor-specific CD4+ Melanoma Tumor-infiltrating Lymphocytes

Cited by 93 publications

References 43 publications

CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes

CD20 alternative splicing isoform generates immunogenic CD4 helper T epitopes

Systematic analysis of CD39, CD103, CD137, and PD‐1 as biomarkers for naturally occurring tumor antigen‐specific TILs

Augmenting the Skin Immune System

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