Self-antigen–specific CD8+ T cell precursor frequency determines the quality of the antitumor immune response

Rizzuto, Gabrielle; Merghoub, Taha; Hirschhorn-Cymerman, Daniel; Liu, Cailian; Lesokhin, Alexander M.; Sahawneh, Diana; Zhong, Hong; Panageas, Katherine S.; Perales, Miguel-Ángel; Altan‐Bonnet, Grégoire; Wolchok, Jedd D.; Houghton, Alan N.

doi:10.1084/jem.20081382

Cited by 94 publications

(124 citation statements)

References 84 publications

(263 reference statements)

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“…Although the magnitude of the TAA-specific CD8 + T cell response (40) and the precursor frequency of TAA-specific T cells (41) correlates with prolonged tumor-free survival in some studies, even very large numbers of TAA-specific T cells do not alter tumor progression in others (42). Therefore, variant peptide vaccines also need to expand an effective portion of the TAAspecific T-cell repertoire, which is dependent on the structure of the variant peptide and the cross-reactivity of the responding T cells (23,24).…”

Section: Discussionmentioning

confidence: 99%

Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens

Jordan

McMahan

Kemmler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Peptide vaccines enhance the response of T cells toward tumor antigens and represent a strategy to augment antigen-independent immunotherapies of cancer. However, peptide vaccines that include native tumor antigens rarely prevent tumor growth. We have assembled a set of peptide variants for a mouse-colon tumor model to determine how to improve T-cell responses. These peptides have similar affinity for MHC molecules, but differ in the affinity of the peptide-MHC/T-cell receptor interaction with a tumor-specific T-cell clone. We systematically demonstrated that effective antitumor responses are generated after vaccination with variant peptides that stimulate the largest proportion of endogenous T cells specific for the native tumor antigen. Importantly, we found some variant peptides that strongly stimulated a specific T-cell clone in vitro, but elicited fewer tumor-specific T cells in vivo, and were not protective. The T cells expanded by the effective vaccines responded to the wild-type antigen by making cytokines and killing target cells, whereas most of the T cells expanded by the ineffective vaccines only responded to the peptide variants. We conclude that peptide-variant vaccines are most effective when the peptides react with a large responsive part of the tumor-specific T-cell repertoire.

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Section: Discussionmentioning

confidence: 99%

Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens

Jordan

McMahan

Kemmler

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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“…Therefore, the presence of MELOE-1-specific T cells in HLA-A2 1 melanoma patients, with a frequency around 1 in 1 Â 10 5 CD8 1 lymphocytes is promising and supports the concept of the development of immunotherapy protocols targeting this antigen. This concept is further strengthened by a recent study demonstrating the functional relevance of CD8 precursor frequencies to tumor immunity [11]. Nonetheless, the presence of MELOE-1-specific T cells in healthy donors at the same frequency than in melanoma patients raised the question of the differentiation status of these lymphocytes.…”

Section: Discussionmentioning

confidence: 95%

“…This antigen is encoded by the meloe gene, overexpressed in human melanoma cell lines, when compared to normal melanocytes, and dramatically underexpressed in other cancer cell lines (colon, renal, breast and lung carcinoma cell lines) and in a variety of normal tissues [10]. This expression profile and the potential involvement of MELOE-1-specific CTL in modifying time to progression of TIL-treated patients strongly suggest that this antigen is a relevant target for the development of immunotherapy protocols in melanoma; however, a crucial point for the use of a tumor antigen in immunotherapy is the presence and frequency of a tumor reactive T-cell-specific repertoire in melanoma patients [11]. Again, with the exception of Melan-A-specific T cells, which are found at high frequencies (up to 1 in 1 Â 10 3 CD8 1 lymphocytes) in the blood of HLA-A2 1 healthy donors and melanoma patients [12][13][14], the frequencies of other antigenspecific T cells are much lower (in the range of 1 in 1 Â 10 7 for MAGE-A3-specific T cells in healthy donors [15]).…”

Section: Introductionmentioning

confidence: 99%

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

et al. 2010

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We recently showed that the infusion of tumor infiltrating lymphocytes specific for the MELOE-1 antigen was associated with a prolonged relapse-free survival for HLA-A2 1 melanoma patients who received tumor infiltrating lymphocytes therapy. Here, we characterized the MELOE-1/A2-specific T-cell repertoire in healthy donors and melanoma patients to further support an immunotherapy targeting this epitope. Using tetramer enrichment followed by multicolor staining, we found that MELOE-1-specific T cells were present in the blood of healthy donors and patients at similar frequencies (around 1 in 1 Â 10 5 CD8 1 cells). These cells mainly displayed a naïve phenotype in 4/6 healthy donors and 3/6 patients, whereas high proportions of memory cells were observed in the remaining individuals of both groups. There was a recurrent usage of the Va12.1 chain for 17/18 MELOE-1-specific T-cell clones derived from healthy donors or patients, associated with diverse Vb chains and V(D)J junctional sequences. All clones derived from melanoma patients (9/9) were reactive against the MELOE-1 36-44 peptide and against HLA-A2 1 melanoma cell lines. This study documents the existence of a large TCR repertoire specific for the MELOE-1/A2 epitope and its capacity to give rise to antitumor CTL that supports the development of immunotherapies targeting this epitope.Key words: Immunotherapy . Melanoma . MELOE-1 . T-cell repertoire . TCR Introduction A key advance in tumor immunology in the past 15 years has been the elucidation of the antigenic basis of tumor cell recognition and destruction, which has opened the way to development of antigen-based immunotherapy in cancer patients. Tumor-associated antigens (TAA) have been grouped into categories according to their expression pattern in neoplastic and normal tissues. TAA can be roughly subdivided into two main classes: proteins expressed specifically by tumor cells, and proteins that are expressed by both tumor cells and by normal cells to a significant level. The first category includes cancergermline antigens, proteins expressed by unconventional gene expression and mutated antigens (see [1] for review). TAA belonging to the second category are the differentiation antigens, mainly expressed in the melanocytic lineage, and the antigens overexpressed by various tumor tissues. Although the immunogenicity of a number of TAA has been documented in clinical Ã These authors contributed equally to this work. We recently showed a correlation between the infusion of T cells reactive against an HLA-A2 epitope derived from another melanoma antigen, MELOE-1, and time to progression of patients treated with autologous tumor infiltrating lymphocytes (TIL) [10]. This antigen is encoded by the meloe gene, overexpressed in human melanoma cell lines, when compared to normal melanocytes, and dramatically underexpressed in other cancer cell lines (colon, renal, breast and lung carcinoma cell lines) and in a variety of normal tissues [10]. This expression profile and the potential involvement of MELOE-1-specific...

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“…10 Moreover, the precursor frequency of naïve T-cells plays a key role. 11 Finally, it is important that T-cells are competent for proliferation, cell survival, homing, effector functions and generation of immunological memory. 8,[12][13][14] Activation of protective CD8 T-cells is best achieved by infection with natural pathogens.…”

mentioning

confidence: 99%

Vaccination‐induced functional competence of circulating human tumor‐specific CD8 T‐cells

Baumgaertner

Jandus

Rivals

et al. 2011

Intl Journal of Cancer

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T‐cells specific for foreign (e.g., viral) antigens can give rise to strong protective immune responses, whereas self/tumor antigen‐specific T‐cells are thought to be less powerful. However, synthetic T‐cell vaccines composed of Melan‐A/MART‐1 peptide, CpG and IFA can induce high frequencies of tumor‐specific CD8 T‐cells in PBMC of melanoma patients. Here we analyzed the functionality of these T‐cells directly ex vivo, by multiparameter flow cytometry. The production of multiple cytokines (IFNγ, TNFα, IL‐2) and upregulation of LAMP‐1 (CD107a) by tumor (Melan‐A/MART‐1) specific T‐cells was comparable to virus (EBV‐BMLF1) specific CD8 T‐cells. Furthermore, phosphorylation of STAT1, STAT5 and ERK1/2, and expression of CD3 zeta chain were similar in tumor‐ and virus‐specific T‐cells, demonstrating functional signaling pathways. Interestingly, high frequencies of functionally competent T‐cells were induced irrespective of patient's age or gender. Finally, CD8 T‐cell function correlated with disease‐free survival. However, this result is preliminary since the study was a Phase I clinical trial. We conclude that human tumor‐specific CD8 T‐cells can reach functional competence in vivo, encouraging further development and Phase III trials assessing the clinical efficacy of robust vaccination strategies.

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Self-antigen–specific CD8+ T cell precursor frequency determines the quality of the antitumor immune response

Cited by 94 publications

References 84 publications

Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens

Peptide vaccines prevent tumor growth by activating T cells that respond to native tumor antigens

Frequent occurrence of high affinity T cells against MELOE‐1 makes this antigen an attractive target for melanoma immunotherapy

Vaccination‐induced functional competence of circulating human tumor‐specific CD8 T‐cells

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