Type I interferon and CD8+ T cell detection help to predict the response to neoadjuvant treatment of rectal adenocarcinoma
Using the TissueFAXS CHROMA multispectral whole-slide scanning platform and StrataQuest image analysis solution, scientists are discovering new, promising biomarkers for the prognosis prediction of a patient’s response to neoadjuvant treatment of rectal cancer. A recent study discovered that the equal weighing of two separate quantifications of type 1 interferon (IFN) expression and CD8+ T cell density is capable of predicting the chances of patients displaying a pathological complete response to neoadjuvant treatment of rectal adenocarcinoma.
Treatment of Rectal Adenocarcinoma
Rectal cancer is among the most common types of cancer worldwide, being the third most common type of cancer in women and the fourth most common type of cancer in men.1 In 2014, in the United States, it was estimated that 40,000 new cases of rectal adenocarcinoma are diagnosed each year.2 However, the management of rectal cancer has shown much improvement over recent decades and is continuing to develop.
Surgical removal of the cancerous tissue is the central treatment for rectal cancer and enhancements in the surgical procedure have improved organ preservation in surgery, resulting in better patient outcomes. Neoadjuvant treatment is also important in helping to optimize surgery outcomes, reducing local reoccurrence and increasing the restriction of radicals. In fact, around 20% of patients have been documented to exhibit a clinical complete response to neoadjuvant treatment with no clinically detectable tumors.3 Together, therapy (such as chemotherapy and radiation) and surgery are the cornerstone approaches to treating rectal adenocarcinoma.
There are important aspects to consider when administering neoadjuvant treatment to patients due to the high risk of very negative, long-term side effects and post-operative complications. An understanding of treatment dosage and patient response is vital to effective, non-toxic neoadjuvant treatment. The dawn of precision medicine is enlightening the neoadjuvant treatment of rectal cancer, allowing for tailor-made treatments and prediction of an individual’s response to the treatment. Thanks to precision medicine, the efficacy of oncology treatments is increasing, while the toxicity of treatments is decreasing, permitting better patient outcomes.
Use of Biomarkers in Rectal Adenocarcinoma Treatment
Precision medicine requires the use of clinically available biomarkers to predict a patient’s response to neoadjuvant treatment. However, there are currently a very limited number of biomarkers available that can accurately discriminate whether patients will respond well or not to the neoadjuvant treatment of rectal cancer. Recently, an examination of the quantity of tumor-infiltrating lymphocytes (TILs) in pre-operative colorectal tumor biopsies resulted in the use of the Immunoscore (IS) as a prognostic indicator of patient survival rates.4
CD8+ TILs density has been proposed to provide an independent predictor of a patient’s complete response to neoadjuvant treatment; however, the results do vary.5 Using the TissueFAXS CHROMA and StrataQuest software, Rezapour et al. investigated the use of TILs as predictive biomarkers of a patient’s response to neoadjuvant treatment of rectal cancer. They did so by examining whether the density and spatial distribution of T cell subsets in pre-operative biopsy samples could predict patients’ responses to neoadjuvant treatment. They also investigated the role of type I IFN in further improving this predictive capacity by measuring the expression of Myxovirus resistance protein A (MxA) used as an indirect marker of type I interferon activity.6
Multiplex immunofluorescence (mIF) Analysis to Identify Predictive Biomarkers for Neoadjuvant Treatment of Rectal Cancer
Multiplex immunofluorescence (mIF) is used to evaluate multiplex images from tumor samples to refine the IS of the predictive biomarker under investigation. Proper evaluation of multiplex images requires special multispectral imaging platforms, such as TissueFAXS CHROMA. TissueFAXS CHROMA is a multispectral whole-slide imaging platform with special SpectraSplit filters that enables the automatic scanning of mIF images and eliminates issues with channel bleed-through. Rezapour et al. used TissueFAXS CHROMA to examine images of stained samples and quantify the density of CD3+ T cells, CD3+CD8+ T cells, CD3+CD8+GrzB+ T cells (active cytotoxic T cells), and γδ T cells per mm2 of the whole tissue, and MxA+ cells per mm2 of stroma. They also used the StrataQuest image analysis solution to detect cell phenotypes and metastructures and acquired numerical values for statistical analysis. After this multiplex image analysis, they correlated the calculated density of the MxA+ T cell subsets , refining the IS.6
Pathological complete response after neoadjuvant treatment was found to be associated with type 1 IFN, assessed by the expression of MxA, independent of the density of CD8+ T cells in the tumor sample. Thus, results indicate the use of MxA expression as a separate predictive biomarker, alongside CD8+ T cells, for the prediction of response to neoadjuvant treatment of rectal adenocarcinoma. An intracohort scoring system, from the equal weighing of two separate quantifications of CD8+ T cells and MxA+ cells in tumor biopsy samples, can be used as a predictive marker for the extent of tumor regression caused by neoadjuvant treatment. Therefore, the independent examination of both CD8+ T cell density and MxA+ cells appears to be a promising approach in helping to identify patients that have a high chance of exhibiting a pathological complete response after neoadjuvant treatment of rectal adenocarcinoma.6
Conclusion
Precision treatment is starting to pave the way in oncology research, with the discovery of predictive biomarkers being central to more effective and less toxic treatments. Thanks to advanced multiplex imaging techniques like TissueFAXS CHROMA and StrataQuest software, the discovery of important predictive biomarkers is becoming ever more viable. Increases in clinically available biomarkers are directing the future of neoadjuvant treatment in oncology, improving the prognosis predictions of individual patients’ responses to the treatments for better patient outcomes.
References
1. Parkin, D.M., Bray, F., Ferlay, J. and Pisani, P. 2005. Global cancer statistics, 2002. CA: a cancer journal for clinicians. 55(2), pp.74-108.
2. Siegel, R., Ma, J., Zou, Z. and Jemal, A. 2014. Cancer statistics, 2014. CA: a cancer journal for clinicians. 64(1), pp.9-29.
3. Dossa, F., Chesney, T.R., Acuna, S.A. and Baxter, N.N. 2017. A watch-and-wait approach for locally advanced rectal cancer after a clinical complete response following neoadjuvant chemoradiation: a systematic review and meta-analysis. The lancet Gastroenterology & hepatology. 2(7), pp.501-513.
4. Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pagès, C., Tosolini, M., Camus, M., Berger, A., Wind, P. and Zinzindohoué, F. 2006. Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science. 313(5795), pp.1960-1964.
5. Farchoukh, L., Hartman, D.J., Ma, C., Celebrezze, J., Medich, D., Bahary, N., Frank, M., Pantanowitz, L. and Pai, R.K. 2021. Intratumoral budding and automated CD8-positive T-cell density in pretreatment biopsies can predict response to neoadjuvant therapy in rectal adenocarcinoma. Modern Pathology. 34(1), pp.171-183.
6. Rezapour, A., Rydbeck, D., Byvald, F., Tasselius, V., Danielsson, G., Angenete, E. and Yrlid, U. 2023. A type I interferon footprint in pre-operative biopsies is an independent biomarker that in combination with CD8+ T cell quantification can improve the prediction of response to neoadjuvant treatment of rectal adenocarcinoma. OncoImmunology. 12(1), p.2209473.
