CD4+ T Cell Help Selectively Enhances High-Avidity Tumor Antigen-Specific CD8+ T Cells

Zhu, Ziqiang; Cuss, Steven; Singh, Vinod; Gurusamy, Devikala; Shoe, Jennifer L.; Leighty, Robert M.; Bronte, Vincenzo; Hurwitz, Arthur A.

doi:10.4049/jimmunol.1401571

Cited by 34 publications

(33 citation statements)

References 31 publications

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“…6). Furthermore, other studies highlighted the importance of CD4 T cell help for CTL activity in improving protection against vaccinia challenge (50,51); however, to our knowledge, this is the first study to suggest that the avidity of Th cells plays a crucial role.…”

Section: Discussionmentioning

confidence: 52%

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Billeskov

Wang

Solaymani-Mohammadi

et al. 2017

The Journal of Immunology

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T cells with high functional avidity can sense and respond to low levels of cognate Ag, a characteristic that is associated with more potent responses against tumors and many infections, including HIV. Although an important determinant of T cell efficacy, it has proven difficult to selectively induce T cells of high functional avidity through vaccination. Attempts to induce high-avidity T cells by low-dose in vivo vaccination failed because this strategy simply gave no response. Instead, selective induction of high-avidity T cells has required in vitro culturing of specific T cells with low Ag concentrations. In this study, we combined low vaccine Ag doses with a novel potent cationic liposomal adjuvant, cationic adjuvant formulation 09, consisting of dimethyldioctadecylammonium liposomes incorporating two immunomodulators (monomycolyl glycerol analog and polyinosinic-polycytidylic acid) that efficiently induces CD4 Th cells, as well as cross-primes CD8 CTL responses. We show that vaccination with low Ag dose selectively primes CD4 T cells of higher functional avidity, whereas CD8 T cell functional avidity was unrelated to vaccine dose in mice. Importantly, CD4 T cells of higher functional avidity induced by low-dose vaccinations showed higher cytokine release per cell and lower inhibitory receptor expression (PD-1, CTLA-4, and the apoptosis-inducing Fas death receptor) compared with their lower-avidity CD4 counterparts. Notably, increased functional CD4 T cell avidity improved antiviral efficacy of CD8 T cells. These data suggest that potent adjuvants, such as cationic adjuvant formulation 09, render low-dose vaccination a feasible and promising approach for generating high-avidity T cells through vaccination.

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Section: Discussionmentioning

confidence: 52%

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Billeskov

Wang

Solaymani-Mohammadi

et al. 2017

The Journal of Immunology

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“…Immunization with a HIF-1α Th1 selective vaccine could inhibit tumor growth in a basal-like transgenic mammary model. The anti-tumor response was mediated by both CD4 and CD8 T-cells, underscoring the role of IFN-γ-secreting Th1 in propagating the generation and expansion of activated CD8 cytotoxic T-cells in the tumor microenvironment (34). …”

Section: Discussionmentioning

confidence: 95%

Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo

Cecil

Slota

O’Meara

et al. 2017

Clinical Cancer Research

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Purpose Triple negative breast cancer (TNBC) represents a cancer stem cell enriched phenotype. Hypoxia-inducible factor-1 alpha (HIF-1α) induces the expression of proteins associated with stemness and is highly upregulated in TNBC. We questioned whether HIF-1α was immunogenic and whether vaccination targeting HIF-1α would impact the growth of basal-like mammary tumors in transgenic mice. Experimental Design We evaluated HIF-1α-specific IgG in sera from controls and patients with breast cancer. Class II epitopes derived from the HIF-1α protein sequence were validated by ELISPOT. To assess therapeutic efficacy, we immunized Tg-MMTVneu and C3(1)Tag mice with HIF-1α Th1-inducing peptides. Stem cells were isolated via magnetic bead separation. Levels of HIF-1α and stem cells in the tumor were quantitated by Western blotting and flow cytometry. Results The magnitude (p<0.001) and incidence (p<0.001) of HIF-1α-specific IgG was elevated in TNBC patients compared to controls. Both breast cancer patients and donors showed evidence of HIF-1α-specific T-helper (Th) 1 and Th2 immunity. Three HIF-1α-specific Th1 class II restricted epitopes that were highly homologous between species elicited Type I immunity in mice. After HIF-1α vaccination, mammary tumor growth was significantly inhibited in only C3(1)Tag (basal-like/stem cellhigh) (p<0.001) not TgMMTV-neu (luminal/neu/stem cell low) (p=0.859) murine models. Vaccination increased Type I T-cells in the tumor (p=0.001) and decreased cells expressing the stem cell marker, Sca-1, compared to controls (p=0.004). Conclusions A HIF-1α vaccine may be uniquely effective in limiting tumor growth in TNBC. Inhibiting outgrowth of breast cancer stem cells via active immunization in the adjuvant setting may impact disease recurrence.

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“…Previous studies have reported several immunization strategies that are capable of eliciting antigen-specific antitumor responses in CD4+ T cell-independent manner, such as supplementing CD40 signals [29] or introducing genes encoding IFN-β [30] or macrophage-derived chemokine [31] in the tumor location. Nonetheless, there is increasing evidence that suggests the need for CD4+ T cells in the generation of effective antitumor immunity, with potential roles such as maintaining the amount of antigen-specific CD8+ T cells, assisting cytotoxic T-lymphocyte (CTL) infiltration into tumor, and enhancing the function of tumor-specific CTLs [32–36]. In our previous study on therapeutic HPV16 DNA vaccine, we observed that IM injection of pNGVL4a-hCRTE6E7L2 DNA vaccine with electroporation can eliminate HPV16-E6/E7-expressing TC-1 tumors in a CD4-depleted setting; however, depletion of CD4 resulted in a lower number of antigen-specific CTLs after immunization [37].…”

Section: Discussionmentioning

confidence: 99%

Characterization of HPV18 E6-specific T cell responses and establishment of HPV18 E6-expressing tumor model

Yang

Peng

et al. 2017

Vaccine

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Human papillomavirus (HPV) has been identified as the primary etiologic factor of cervical cancer, and subsets of anogenital and oropharyngeal cancers. HPV18 is the second most prevalent high-risk HPV type after HPV16. Furthermore, HPV18 is responsible for approximately 12% of cervical squamous cell carcinoma and 37% of cervical adenocarcinoma cases worldwide. In this study, we aimed to characterize the HPV18-E6-specific epitope and establish an HPV18 animal tumor model to evaluate the E6-specific immune response induced by our DNA vaccine. We vaccinated naïve C57BL/6 mice with a prototype DNA vaccine, pcDNA3-HPV18-E6, via intramuscular injection followed by electroporation, and analyzed the E6-specific CD8+ T cell responses by flow cytometry using a reported T cell epitope. We then characterized the MHC restriction element for the characterized HPV18-E6 epitope. Additionally, we generated an HPV18-E6-expressing tumor cell line to study the antitumor effect mediated by E6-specific immunity. We observed a robust HPV18-E6aa67-75 peptide-specific CD8+ T cell response after vaccination with pcDNA3-HPV18-E6. Further characterization demonstrated that this epitope was mainly restricted by H-2Kb, but was also weakly presented by HLA-A*0201, as previously reported. We observed that vaccination with pcDNA3-HPV18-E6 significantly inhibited the growth of HPV18-E6-expressing tumor cells, TC-1/HPV18-E6, in mice. An antibody depletion study demonstrated that both CD4+ and CD8+ T cells are necessary for the observed antitumor immunity. The characterization of HPV18-E6-specific T cell responses and the establishment of HPV18-E6-expressing tumor cell line provide infrastructures for further development of HPV18-E6 targeted immunotherapy.

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CD4+ T Cell Help Selectively Enhances High-Avidity Tumor Antigen-Specific CD8+ T Cells

Cited by 34 publications

References 31 publications

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Low Antigen Dose in Adjuvant-Based Vaccination Selectively Induces CD4 T Cells with Enhanced Functional Avidity and Protective Efficacy

Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo

Characterization of HPV18 E6-specific T cell responses and establishment of HPV18 E6-expressing tumor model

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