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. 2024 Sep 25;13(1):2407532.
doi: 10.1080/2162402X.2024.2407532. eCollection 2024.

Enhancing T-cell recruitment in renal cell carcinoma with cytokine-armed adenoviruses

Michaela Feodoroff  1   2   3   4   5 , Firas Hamdan  1   3   4 , Gabriella Antignani  1   3   4 , Sara Feola  1   3   4 , Manlio Fusciello  1   3   4 , Salvatore Russo  1   3   4 , Jacopo Chiaro  1   3   4 , Katja Välimäki  2 , Teijo Pellinen  2   5 , Rui M Branca  6 , Janne Lehtiö  6 , Federica D Alessio  1   3   4 , Paolo Bottega  1   3   4 , Virpi Stigzelius  1   3   4 , Janita Sandberg  1   3   4 , Jonna Clancy  7 , Jukka Partanen  7 , Minna Malmstedt  5   8   9 , Antti Rannikko  5   8   9 , Vilja Pietiäinen  2   5 , Mikaela Grönholm  1   3   4   5 , Vincenzo Cerullo  1   3   4   5   10
Affiliations

Enhancing T-cell recruitment in renal cell carcinoma with cytokine-armed adenoviruses

Michaela Feodoroff et al. Oncoimmunology. .

Abstract

Immunotherapy has emerged as a promising approach for cancer treatment, with oncolytic adenoviruses showing power as immunotherapeutic agents. In this study, we investigated the immunotherapeutic potential of an adenovirus construct expressing CXCL9, CXCL10, or IL-15 in clear cell renal cell carcinoma (ccRCC) tumor models. Our results demonstrated robust cytokine secretion upon viral treatment, suggesting effective transgene expression. Subsequent analysis using resistance-based transwell migration and microfluidic chip assays demonstrated increased T-cell migration in response to chemokine secretion by infected cells in both 2D and 3D cell models. Flow cytometry analysis revealed CXCR3 receptor expression across T-cell subsets, with the highest percentage found on CD8+ T-cells, underscoring their key role in immune cell migration. Alongside T-cells, we also detected NK-cells in the tumors of immunocompromised mice treated with cytokine-encoding adenoviruses. Furthermore, we identified potential immunogenic antigens that may enhance the efficacy and specificity of our armed oncolytic adenoviruses in ccRCC. Overall, our findings using ccRCC cell line, in vivo humanized mice, physiologically relevant PDCs in 2D and patient-derived organoids (PDOs) in 3D suggest that chemokine-armed adenoviruses hold promise for enhancing T-cell migration and improving immunotherapy outcomes in ccRCC. Our study contributes to the development of more effective ccRCC treatment strategies by elucidating immune cell infiltration and activation mechanisms within the tumor microenvironment (TME) and highlights the usefulness of PDOs for predicting clinical relevance and validating novel immunotherapeutic approaches. Overall, our research offers insights into the rational design and optimization of viral-based immunotherapies for ccRCC.

Keywords: Cytokines; immunotherapy; oncolytic viruses; renal cell carcinoma; tumor peptides.

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Conflict of interest statement

Oncolytic viruses encoding for cytokines CXCL9, CXCL10 and IL-15 have been licensed to Ximbio/CancerTools.org for commercialization to other academic or commercial researchers. V.S. is currently employed by AstraZeneca. V.C is a co-founder and shareholder at VALO Therapeutics. Other authors report there are no competing interests to declare.

Figures

Figure 1.
Figure 1.
Characterization of oncolytic fitness in CXCL9, CXCL10 and IL-15 expressing viruses.
Figure 2.
Figure 2.
CXCR3 receptor expression on human PBMCs and PBMC migration in transwell system.
Figure 3.
Figure 3.
Migration of PBMCs in in vivo mouse models treated with oncolytic adenovirus.
Figure 4.
Figure 4.
Migration of PBMCs in in vivo mouse models treated with oncolytic adenovirus and anti-PD-1.
Figure 5.
Figure 5.
Immunofluorescence staining, Ad5-Δ24-RFP infection and PBMC migration in PDOs.
Figure 6.
Figure 6.
Peptide distribution, response and killing of ccRCC cells.
See this image and copyright information in PMC

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