High Frequency of Autologous Anti-Melanoma CTL Directed Against an Antigen Generated by a Point Mutation in a New Helicase Gene

Baurain, Jean‐François; Colau, Didier; Baren, Nicolas van; Landry, Claire; Martelange, Valérie; Vikkula, Miikka; Boon, Thierry; Coulie, Pierre G.

doi:10.4049/jimmunol.164.11.6057

Cited by 85 publications

(52 citation statements)

References 53 publications

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“…Furthermore, immunizations targeting MHC class I-restricted mutated tumor peptides in animal cancer models have been reported to induce tumor rejection (34 -38). These results from animal cancer models and recent observations in humans supporting a correlation between the presence of CTL specific for unique tumor mutations and good survival rate (4,5) suggest that HLA class I-restricted mutated epitopes might be the best Ags to target. In this respect, oncogenic mutations may be especially good target Ags, as far as CTL killing of tumor cells expressing the oncogene would lead to a direct tumor growth disadvantage, even if Ag loss variant tumor cells are not eradicated.…”

Section: Discussionsupporting

confidence: 51%

“…In humans, although many tumor-associated Ags have recently been identified and although many epitopes from these are currently being used in immunotherapy trials, none of these has yet reached the status of tumor rejection Ags. CTL recognition of unique mutations of tumor cell proteins have been reported to be associated with unusually favorable clinical evolution in melanoma lesions, suggesting that mutated Ags could play such a role (4,5). CD8 ϩ CTL have been implicated as important cellular components involved in the recognition and eradication of tumor cells in both murine and human systems (6,7).…”

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confidence: 99%

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A ras-Mutated Peptide Targeted by CTL Infiltrating a Human Melanoma Lesion

Linard

Bézieau

Benlalam

et al. 2002

The Journal of Immunology

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Ags derived from commonly mutated oncogenic proteins seem ideally suited as targets for tumor immunotherapy. Nonetheless, only a few mutated epitopes efficiently presented by human tumors have thus far been identified. We describe here an approach to identify such epitopes. This approach involves: 1) identifying tumors expressing a ras mutation and isolating the tumor-infiltrating lymphocytes (TIL); 2) transfecting COS cells to induce expression of unknown mutated peptides in the context of a patient’s HLA class I molecules; and 3) screening epitope recognition by using TIL from the tumors expressing a ras mutation. By using this approach, there appeared to be a N-ras mutation (a glutamine-to-arginine exchange at residue 61 (Q61R)), detected in a melanoma lesion, which was recognized specifically by the autologous TIL in the HLA-A*0101 context. The ras peptide 55–64Q61R was the epitope of these TIL and was regularly presented by Q61R-mutated HLA-A*0101+ melanoma cell lines. This peptide and its wild-type homolog (55–64wt) bound to HLA-A*0101 with similar affinities. However, only the mutated peptide could induce specific CTL expansion from PBL. All the CTL clones specific to the mutated peptide, failed to recognize the wild-type sequence on both COS and melanoma cells. These data thus show that oncogenic protein mutations can create shared tumor-specific CTL epitopes, efficiently presented by tumor cells, and that screening for oncogene-transfected COS cell recognition by TIL (from tumors containing mutations) is a powerful approach for the identification of these epitopes.

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Section: Discussionsupporting

confidence: 51%

mentioning

confidence: 99%

A ras-Mutated Peptide Targeted by CTL Infiltrating a Human Melanoma Lesion

Linard

Bézieau

Benlalam

et al. 2002

The Journal of Immunology

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“…As yet no truly successful anti-melanoma vaccine has been developed, although various strategies have been tested. In general, numerous tumour-reactive T lymphocytes can be detected in the patient's blood following vaccination, but tumour growth is unaffected (Arienti et al, 1996;Lee et al, 1998;Baurain et al, 2000;Appay et al, 2006). One explanation is that the tumour microenvironment is so immunosuppressive that any incoming effector cell is impeded (Appay et al, 2006).…”

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confidence: 99%

Mechanisms of local immunosuppression in cutaneous melanoma

et al. 2007

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Cutaneous melanoma is highly immunogenic, yet primary melanomas and metastases develop successfully in otherwise immunocompetent patients. To investigate the local immunosuppressive microenvironment, we examined the presence of suppressor T lymphocytes and tolerising dendritic cells (DCs), the expression of immunosuppressive cytokines (IL-10, TGFb1 and TGFb2) and the enzyme indoleamine 2,3-dioxygenase (IDO) using qRT -PCR and immunohistochemistry in primary skin melanomas, negative and positive sentinel lymph nodes (SLN), and lymph nodes with advanced metastases. Our results indicate that tolerogenic DCs and suppressor T lymphocytes are present in melanoma at all stages of disease progression. They express transforming growth factor b receptor 1 (TGFbR1), and are therefore susceptible to TGFb1 and TGFb2 specifically expressed by primary melanoma. We found that expression of IDO and interleukin 10 (IL-10) increased with melanoma progression, with the highest concentration in positive SLN. We suggest that negative SLN contain immunosuppressive cells and cytokines, due to preconditioning by tolerogenic DCs migrating from the primary melanoma site to the SLN. In primary melanoma, TGFb2 is likely to render peripheral DCs tolerogenic, while in lymph nodes IDO and TGFb1 may have a major effect. This mechanism of tumourassociated immunosuppression may inhibit the immune response to the tumour and may explain the discrepancy between the induction of systemic immunity by anti-melanoma vaccines and their poor performance in the clinic.

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“…These data, together with previous findings showing a correlation between T cell-mediated immunity involving mutated Ags and positive clinical evolution in vaccinated cancer patients (41,42), encourage novel efforts for the development of a cancer vaccine based on the usage of tumor-specific and class II-HLA-restricted Ags.…”

Section: Discussionmentioning

confidence: 97%

Identification of a Mutated Receptor-Like Protein Tyrosine Phosphatase κ as a Novel, Class II HLA-Restricted Melanoma Antigen

Novellino¹,

Renkvist²,

Rini³

et al. 2003

The Journal of Immunology

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Recent studies increasingly point to a pivotal role of CD4+ T cells in human anti-tumor immune response. Here we show that lymphocytes purified from a tumor-infiltrated lymph node of a melanoma patient that had remained disease free for 10 years after surgical resection of a lymph node metastasis comprised oligoclonal class II HLA-restricted CD4+ T cells recognizing the autologous tumor cells in vitro. In fact, the CD4+ T cell clones isolated from these lymphocytes displayed a tumor-specific, cytotoxic activity in addition to a Th1-like cytokine profile. By a genetic approach, a peptide derived from a mutated receptor-like protein tyrosine phosphatase κ was identified as a novel HLA-DR10-restricted epitope for all the melanoma-specific CD4+ T cell clones. The immunogenic peptide was shown to contain the mutated residue that was crucial for T cell recognition and activation. Moreover, a systemic immunity against the mutated peptide was detectable in the patient’s peripheral blood T lymphocytes obtained during the disease-free period of follow-up. These findings further support the relevance of CD4+ T cells directed against mutated epitopes in tumor immunity and provide the rationale for a possible usage of mutated, tumor-specific Ags for immunotherapy of human cancer.

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High Frequency of Autologous Anti-Melanoma CTL Directed Against an Antigen Generated by a Point Mutation in a New Helicase Gene

Cited by 85 publications

References 53 publications

A ras-Mutated Peptide Targeted by CTL Infiltrating a Human Melanoma Lesion

A ras-Mutated Peptide Targeted by CTL Infiltrating a Human Melanoma Lesion

Mechanisms of local immunosuppression in cutaneous melanoma

Identification of a Mutated Receptor-Like Protein Tyrosine Phosphatase κ as a Novel, Class II HLA-Restricted Melanoma Antigen

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