A correlation between in vivo and in vitro virus control mediated by CD8+ T-cell populations has been demonstrated by CD8 T-cell-mediated inhibition of HIV-1 and SIV replication in vitro in ...peripheral blood mononuclear cells (PBMCs) from infected humans and non-human primates (NHPs), respectively. Here, the breadth and specificity of T-cell responses induced following vaccination with replication-defective adenovirus serotype 35 (Ad35) vectors containing a fusion protein of Gag, reverse transcriptase (RT), Integrase (Int) and Nef (Ad35-GRIN) and Env (Ad35-ENV), derived from HIV-1 subtype A isolates, was assessed in 25 individuals. The vaccine induced responses to a median of 4 epitopes per vaccinee. We correlated the CD8 responses to conserved vs. variable regions with the ability to inhibit a panel of 7 HIV-1 isolates representing multiple clades in a virus inhibition assay (VIA). The results indicate that targeting immunodominant responses to highly conserved regions of the HIV-1 proteome may result in an increased ability to inhibit multiple clades of HIV-1 in vitro. The data further validate the use of the VIA to screen and select future HIV vaccine candidates. Moreover, our data suggest that future T cell-focused vaccine design should aim to induce immunodominant responses to highly conserved regions of the virus.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Abstract
Murine tissues harbour signature, resident γδ T cell compartments with profound yet differential impacts on carcinogenesis. γδ T cell knockout mice have heightened susceptibility to ...carcinogenesis. However, it is now clear in the murine setting that IFNγ-producing γδ T cells reject tumours whilst IL-17-producing γδ T cells promote them. Nonetheless, many human γδ T cell compartments are distinct from that in mice and vice versa. The extent to which human tissues and tumours harbour resident γδ T cells, their effector function and their role in cancer is less clear. Although a large scale in silico study of 5000+ patients with cancer found that intratumoural γδ T cells were the most important correlate of survival, smaller studies have found that these cells to be associated with either survival or progression. Many historical studies have however been limited by the availability of technologies to rigorously identify, isolate, and examine tissue-resident γδ T cells.
To address these issues, we present data from stage I-III non-small cell lung cancers and paired non-tumour (NT) tissue obtained at primary surgery from 25 patients enrolled in the TRACERx Study. Using flow cytometry and quantitative T cell receptor sequencing, we demonstrate that NT lung tissues harbour a resident population of Vδ1 γδ T cells, entirely distinct to blood. Compared with NT lung tissues, resident-memory and effector-memory Vδ1 T cells are enriched in tumours. RNA sequencing revealed that intratumoural Vδ1 T cells are skewed towards cytolysis and T-helper-1 functions, akin to intratumoural NK and CD8+ T cells. Importantly, we found no evidence of T-helper-17 skew that has been implicated in tumour promotion in murine models. Ongoing remission after surgery was significantly associated with the presence of CD103+ tissue-resident Vδ1 T cells in non-malignant lung tissues and the presence of CD45RA-/CD27+ effector-memory Vδ1 T cells in tumours. Moreover, patients with a greater proportion of intratumoural Vδ1 T cell clones shared with paired NT tissues were more likely to remain in remission, consistent with the cells’ proposed immunosurveillance function in steady state epithelial tissues.
Whilst immunotherapies modulating αβ T cells have been successful for some patients, including those with non-small cell lung cancer, clinical trials of γδ T cells have so far demonstrated poor efficacy in solid cancers. These trials have hitherto exclusively utilised Vδ2 T cells, a subset which is found predominantly in peripheral blood and more commonly associated, albeit still rarely, with IL-17 production. The first-in-human clinical trial of Vδ1 T cell immunotherapy has just opened for patients with acute myeloid leukaemia. Thus, our findings have immediate translational relevance and support the utilisation of these as-yet-untapped Vδ1 T cells in solid cancer immunotherapy.
Citation Format: Yin Wu, Dhruva Biswas, Ieva Usaite, Angelova Mihaela, Stefan Boeing, Takahiro Karasaki, Selvaraju Veeriah, Justyna Czyzewska-Khan, James Reading, Andrew Georgiou, Maise Al-Bakir, Nicholas McGranahan, Mariam Jamal-Hanjani, Allan Hackshaw, TRACERx Consortium, Sergio Quezada, Adrian Hayday, Charles Swanton. V-delta-1 T cells are resident in the human lung and associate with survival in patients with non-small cell lung cancer in the TRACERx Study abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5636.
A correlation between in vivo and in vitro virus control mediated by CD8+ T-cell populations has been demonstrated by CD8 T-cell-mediated inhibition of HIV-1 and SIV replication in vitro in ...peripheral blood mononuclear cells (PBMCs) from infected humans and non-human primates (NHPs), respectively. Here, the breadth and specificity of T-cell responses induced following vaccination with replication-defective adenovirus serotype 35 (Ad35) vectors containing a fusion protein of Gag, reverse transcriptase (RT), Integrase (Int) and Nef (Ad35-GRIN) and Env (Ad35-ENV), derived from HIV-1 subtype A isolates, was assessed in 25 individuals. The vaccine induced responses to a median of 4 epitopes per vaccinee. We correlated the CD8 responses to conserved vs. variable regions with the ability to inhibit a panel of 7 HIV-1 isolates representing multiple clades in a virus inhibition assay (VIA). The results indicate that targeting immunodominant responses to highly conserved regions of the HIV-1 proteome may result in an increased ability to inhibit multiple clades of HIV-1 in vitro. The data further validate the use of the VIA to screen and select future HIV vaccine candidates. Moreover, our data suggest that future T cell-focused vaccine design should aim to induce immunodominant responses to highly conserved regions of the virus.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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