Measuring Intratumoral Heterogeneity of Immune Repertoires

Yuzhakova, Diana V.; Volchkova, Lilia N; Pogorelyy, Mikhail V.; Serebrovskaya, Ekaterina O.; Shagina, Irina; Bryushkova, Ekaterina A.; Nakonechnaya, Tatiana O; Izosimova, Anna V.; Zavyalova, Daria S; Karabut, Maria; Izraelson, Mark; Samoylenko, Igor; Загайнов, В. Е.; Chudakov, Dmitriy M.; Zagaynova, Elena V.; Sharonov, George V

doi:10.3389/fonc.2020.00512

Cited by 16 publications

(13 citation statements)

References 53 publications

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“…It is also likely that dose and scheduling for improved immune and patient responses are disease-and treatment-specific (8,37), reflecting current recommendations for curtailing tumor growth that are dependent on the targeted tissue and disease. Available tissue was restricted to small regions within patient tumors (∼1 g), and thus we were unable to capture the well-characterized tumor heterogeneity within RCC and other tumor types (38,39). In addition, while we did observe peripheral changes to T cell repertoires following treatment, the duration of contraction and tumor-enriched clone frequency was not evaluated past 4 wk due to the nature of the study.…”

Section: Discussionmentioning

confidence: 98%

Radiation induces dynamic changes to the T cell repertoire in renal cell carcinoma patients

Chow

Hoffend

Abrams

et al. 2020

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

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Clinical studies combining radiation and immunotherapy have shown promising response rates, strengthening efforts to sensitize tumors to immune-mediated attack. Thus, there is an ongoing surge in trials using preconditioning regimens with immunotherapy. Yet, due to the scarcity of resected tumors treated in situ with radiotherapy, there has been little investigation of radiation’s sole contributions to local and systemic antitumor immunity in patients. Without this access, translational studies have been limited to evaluating circulating immune subsets and systemic remodeling of peripheral T cell receptor repertoires. This constraint has left gaps in how radiation impacts intratumoral responses and whether tumor-resident T cell clones are amplified following treatment. Therefore, to interrogate the immune impact of radiation on the tumor microenvironment and test the hypothesis that radiation initiates local and systemic expansion of tumor-resident clones, we analyzed renal cell carcinomas from patients treated with stereotactic body radiation therapy. Transcriptomic comparisons were evaluated by bulk RNA sequencing. T cell receptor sequencing monitored repertoires during treatment. Pathway analysis showed radiation-specific enrichment of immune-related processes, and T cell receptor sequencing revealed increased clonality in radiation-treated tumors. The frequency of identified, tumor-enriched clonotypes was tracked across serial blood samples. We observed increased abundance of tumor-enriched clonotypes at 2 wk postradiation compared with pretreatment levels; however, this expansion was not sustained, and levels contracted toward baseline by 4 wk posttreatment. Taken together, these results indicate robust intratumoral immune remodeling and a window of tumor-resident T cell expansion following radiation that may be leveraged for the rational design of combinatorial strategies.

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Section: Discussionmentioning

confidence: 98%

Radiation induces dynamic changes to the T cell repertoire in renal cell carcinoma patients

Chow

Hoffend

Abrams

et al. 2020

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

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“…A previous study has shown that there is intratumoral heterogeneity of the TCR repertoire ( 30 ). When extrapolating our bilateral tumor model to a clinical situation, where antitumor immune responses are longitudinally monitored by tumor biopsy, it is important to determine whether the difference in TCR repertoire between the bilateral tumors could be considered equivalent to that within one side of the tumor.…”

Section: Resultsmentioning

confidence: 99%

Proportional Tumor Infiltration of T Cells via Circulation Duplicates the T Cell Receptor Repertoire in a Bilateral Tumor Mouse Model

et al. 2021

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Temporal analysis of the T cell receptor (TCR) repertoire has been used to monitor treatment-induced changes in antigen-specific T cells in patients with cancer. However, the lack of experimental models that allow a temporal analysis of the TCR repertoire in the same individual in a homogeneous population limits the understanding of the causal relationship between changes in TCR repertoire and antitumor responses. A bilateral tumor model, where tumor cells were inoculated bilaterally into the backs of mice, could be used for temporal analysis of the TCR repertoire. This study examined the prerequisite for this strategy: the TCR repertoire is conserved between bilateral tumors that grow symmetrically. Bilateral tumors and draining lymph nodes (dLNs) were collected 13 days after tumor inoculation to analyze the TCR repertoire of CD4+ and CD8+ T cells. The tumor-infiltrating T-cell clones were highly similar between the bilateral tumors and expanded to a similar extent. In addition, the differences of TCR repertoire between the bilateral tumors were equivalent to Intra-tumoral heterogeneity on one side. On the other hand, the similarity of the TCR repertoire in the bilateral dLNs was markedly lower than that in the tumor, suggesting that tumor-reactive T cell clones induced independently in each dLN are mixed during recirculation and then proportionally infiltrated the bilateral tumors. These findings provide the basis for future analysis of temporal and treatment-induced changes in tumor-reactive T cell clones using this bilateral tumor model.

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“…Previous studies have shown that there is intratumoral heterogeneity of the TCR repertoire (20). When extrapolating our bilateral tumor model to a clinical situation, where antitumor immune responses are longitudinally monitored by tumor biopsy, it is important to determine whether the difference in TCR repertoire between the bilateral tumors could be considered equivalent to that within one side of the tumor.…”

Section: Resultsmentioning

confidence: 99%

T cell receptor (TCR) repertoire analysis reveals a highly conserved TCR repertoire in a bilateral tumor mouse model

Tsunoda

Aoki

Shimizu

et al. 2021

Preprint

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Temporal analysis of the T cell receptor (TCR) repertoire has been used to monitor treatment-induced changes in antigen-specific T cells in patients with cancer. However, the lack of experimental models that allow temporal analysis of the TCR repertoire in the same individual in a homogeneous population limits the understanding of the causal relationship between changes in TCR repertoire and antitumor responses. A bilateral tumor model, where tumor cells were inoculated bilaterally into the backs of mice, could be used for temporal analysis of the TCR repertoire. This study examined the prerequisite for this strategy: the TCR repertoire is conserved between bilateral tumors with the same growth rate. Bilateral tumors with equivalent size and draining lymph nodes (dLNs) were collected 13 days after tumor inoculation to analyze the TCR repertoire of CD4+ and CD8+ T cells. The tumor-infiltrating T cell clones were highly conserved between the bilateral tumors, and the extent of clonal expansion was equivalent. In addition, the similarity between the bilateral tumors was equivalent to heterogeneity on one side of the tumor. The similarity of the TCR repertoire in the bilateral dLNs was markedly lower than that in the tumor, suggesting that tumor-reactive T cell clones induced independently in each dLN integrated during recirculation and then infiltrated the tumor. These findings suggest that our bilateral tumor model is suitable for temporal monitoring of the TCR repertoire to evaluate temporal and treatment-induced changes in tumor-reactive T cell clones.

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Measuring Intratumoral Heterogeneity of Immune Repertoires

Cited by 16 publications

References 53 publications

Radiation induces dynamic changes to the T cell repertoire in renal cell carcinoma patients

Radiation induces dynamic changes to the T cell repertoire in renal cell carcinoma patients

Proportional Tumor Infiltration of T Cells via Circulation Duplicates the T Cell Receptor Repertoire in a Bilateral Tumor Mouse Model

T cell receptor (TCR) repertoire analysis reveals a highly conserved TCR repertoire in a bilateral tumor mouse model

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