Cytokine/chemokine profiles in squamous cell carcinoma correlate with precancerous and cancerous disease stage

Abstract

Actinic Keratosis (AK), Intraepidermal Carcinoma (IEC), and Squamous Cell Carcinoma (SCC) are generally considered to be advancing stages of the same disease spectrum. However, while AK often regress spontaneously, and IEC often regress in response to immune-activating treatments, SCC typically do not regress. Therefore, it is vital to define whether fundamental immunological changes occur during progression to SCC. Here we show that proinflammatory cytokine expression, chemokine expression, and immune cell infiltration density change during progression to SCC. Our findings suggest a switch from predominantly proinflammatory cytokine production to chemokine production is a key feature of progression from precancer to cancer. Together, these observations propose a model that can underpin current research and open new avenues of exploration into the clinical significance of these profiles with respect to immunotherapeutic or other treatment outcomes.

IFN-γ Critically Enables the Intratumoural Infiltration of CXCR3+ CD8+ T Cells to Drive Squamous Cell Carcinoma Regression

“…Recently, we conducted a study of the cytokine and chemokine environment within advancing stages of the SCC disease spectrum in patients [ 7 ]. Samples taken from Actinic Keratosis, considered to be a premalignant or precancerous form of SCC associated with a high rate of spontaneous regression, indicated significant increases in several proinflammatory cytokines (e.g., IFN-γ, TNF-α, IL-1β, IL-17A, IFN-α, IL-12p70) when compared to photodamaged skin at the protein level.…”

“…Our data indicate, however, that antibody-treated mice did show reduced CXCL9, CXCL10, and CCL5 chemokine production within the tumour mass, and a corresponding reduction in the number of tumour-infiltrating T cells. The CXCR3-ligands CXCL9, CXCL10, and CXCL11 all increase in abundance with advancing SCC disease stage in humans [ 7 ]. In our model, mice treated with an antibody to block the binding of CXCL10 and CXCL11 to CXCR3 (but not the binding of CXCL9 to CXCR3 [ 29 ]) were unable to control the growth of established tumours.…”

“…Indeed, solid organ transplant recipients suffer a 65–100-fold increased incidence of SCC as a consequence of the immunosuppressive medications they must take to prevent organ rejection [ 3 , 4 , 5 ], highlighting the strong association between immune function and the emergence of SCC. Several groups including our own have reported that SCC tumours contain a strong abundance of immune cells, inflammatory cytokines, and target antigens [ 6 , 7 , 8 , 9 , 10 , 11 ], and can therefore be considered to be immunologically ‘hot’ tumours. However, despite the presence of an inflammatory environment, SCC tumours rarely regress, and the standard of care is surgical removal in order to prevent progression to metastatic disease.…”

“…The presence of an inflammatory microenvironment within SCC lesions is well documented [ 7 , 19 , 20 ]. IFN-regulated gene transcription is increased and correlates with the extent of immune cell infiltration, suggesting that IFN-associated immune responses play an important role in SCC immunosurveillance [ 19 ].…”

Predicting and Preventing Immune Checkpoint Inhibitor Toxicity: Targeting Cytokines

“…Induction of cytokines both preceding and during CPI treatment might enable the identification of biomarkers that assist in advancing clinical monitoring for the development and severity of irAEswhich remains a significant challenge because of their precipitous and variable onset. However, multiple factors such as the location and severity of irAEs, the type of therapeutic response and CPI exposure, as well as the tumor type and metastatic burden, should all be considered when assessing the cytokine response in the development of irAEs [11,12,19,20]. Serial testing of cytokines to establish their dynamic range during CPI treatment may help to unravel their association with irAEs and define possible therapeutic avenues to mitigate immunotoxicity.…”