Precision Medicine as a Potential Weapon
The ability to be truly oneself arises from the freedom to exude individuality, expressing one’s experiences, thoughts, ideas, and background in any way they choose. It is what makes us diverse, and this diversity filters into the body—its appearance and genetic variation. While the development of healthcare in its initial stages sought to cater to the masses, and help as many people as possible with each breakthrough, more recent research has delved into precision medicine. Precision medicine aims to cater to every individual based on their characteristics, and is a more complex and ambitious outlook to medicine. Variabilities in response to treatment methods include the individual’s lifestyle, such as diet and regular medications, phenotype such as weight, ethnicity, as well as genotype of the individual, which could have which are variations in a DNA sequences in regions of interest.[1] Dr Hannah Carter at the UC San Diego School of Medicine is one such researcher who is interested in precision medicine, and some of her exciting work is in the field of cancer immunotherapy.
An Introduction to the Enemy
Cancer, or ‘The Emperor of All Maladies,’ as Siddhartha Mukherjee coined it, has been an ubiquitous health concern since 2500 B.C.[2] It is characterized by an uncontrolled growth of cells in the body due to failure of cell cycle regulation.[3] This disease overrides healthy functioning of the immune system, especially its ability to impede cell proliferation. In an attempt to better tackle the disease, the scientific community seeks to understand tumor growth, tumor interactions with cells in the body, and the genes of the immune system. With more clarity on the genetics of the immune system in relation to cancers and tumor growth, immunotherapy techniques can be modified for better, more personalized patient care.
Building the Weapon: Tumors, TIME and eQTLs
While the field of immunotherapy has expanded over the years, one drawback has been low response rates to current immunotherapies, with no definitive cause.[4] The Carter Lab believes that the potential of immunotherapy could be recognized in part by delving into the tumor immune microenvironment (TIME).[4] This microenvironment consists of both inhibitors as well as supporters of tumor growth, and learning from each body’s response could help develop therapies to attack the TIME.[5] One family of components in TIME is immune infiltrates, which are immune cells that enter the tumor from the bloodstream.[6, 7] In Dr. Carter’s research, TIME was described through a collection of immune phenotype (IP) components that included immune infiltrating cells, measured from gene expression levels.[4]
Summary: The Research Approach
On understanding the key terms in Dr. Carter’s research, a more thorough look reveals the group’s aims — elucidating cancer risk, survival, as well as response to a method of immunotherapy known as Immune Checkpoint Blockade (ICB).[4] While providing potential targets for immunotherapy, Dr. Carter also tests her computational models using different datasets, and uses in-vivo mouse models to test other targets.[4] As a broad framework, their research first identifies genes and IPs of interest before narrowing in on eQTLs of interest.[4] The research specifically identifies TIME eQTLs and analyzes them downstream for correlations across different cancers and tumor types.[4] Further, the research delves into predicting cancer risk using inferred associations, along with survival rates.[4] To address the response to current ICB immunotherapies as well, analysis was done across different studies to check for strong association of eQTLs identified with ICB response.[4] In addition to identifying eQTLs, their correlation with risk, survival and therapy response, the lab built a model to assess the potential for immune genetics to affect the three main areas of focus and yield potential targets, and tested this model on different cohorts and cancer types.[4]
Connecting TIME eQTLs to Cancer Risk, Survival and Immunotherapy Response
To determine contributions of TIME to tumor development and possible immunotherapy approaches, initial analysis included identification of heritable characteristics (ones that could contribute to the phenotype) in TIME that could affect tumor immune responses.[4] On normalization and analysis, 733 total IP components of interest were derived from an atlas of data of over 11,000 patients’ tumor and matched normal samples, identified across 30 different cancer types known as The Cancer Genome Atlas.[4] 32% of these could potentially be SNP-heritable, meaning that 32% of these components could significantly influence the phenotype (expressed as the TIME).[4] However, since a majority of these IPs did not pass a threshold for such heritability, researchers looked at a subset of 157 heritable immune genes that were SNP-heritability associated.[4] A genome wide association study (GWAS) was conducted on these remaining genes, which identified frequent variations found in diseased samples when compared to healthy samples.[4] From this GWAS study, 890 TIME eQTLs were identified.[4] On analysis of the genes of interest identified, genes of macrophages (immune system components that which engulf foreign cells) and lymphocytes (produce antibodies) were found in the highest quantity.[4] Additionally, a large correlation was seen in genes coding for MHC complexes, which are responsible for antigen presentation.[4] The majority of the eQTLs are not cancer-type-specific, and of the 890 TIME eQTLs identified, only one (rs146336885) was specific to tumor type.[4] Dr. Carter’s group used analysis methods in human cohort datasets such as TCGA and other databases such as UK Biobank to assess that eQTLs were relevant to existing cancer data, and not just simply gene expression.[4]
Using Polygenic Score Models
To assess cancer risk with TIME eQTLs, researchers used polygenic risk scores, which are models to predict the potential risk of developing a disease based on given genetic information of an individual. This research looked at two different cancer types—melanoma and prostate cancers; melanoma is a cancer type with tumors containing high amounts of immune infiltrates and good response to immunotherapy, while prostate cancer has low amounts of immune infiltrates and poor immunotherapy response.[4, 9, 10] Risk scores for developing both cancers were significantly different in the top 10% and bottom 10% of population.[4] Further, eQTLs related to a gene of interest, CTSS, and MHC genes were considered most important in both cancer types.[4] Similarly promising results were seen for patient survival when tested using Polygenic survival scores.[4]
Dr. Carter’s Other Projects: More Applications for Precision Medicine
Immunotherapy is one of many types of treatments for cancer and Dr. Carter’s work looks at other forms of precision cancer therapies. One such widely used approach that contributes to almost 40% of cancer treatments is radiation therapy. In collaboration with Dr. Vitali Moiseenko, the Carter Lab worked to identify the biomarkers correlated with post-radiation toxicity, an array of side effects caused by penetrating radiation therapy.[11] Head and neck squamous cell carcinoma patients at the Moores Cancer Center at UC San Diego were studied with somatic tumor sample sequencing and transcriptome RNA-seq amongst other methods.[11]
Implications for Future Battles
While this research is a promising step in the path to precision medicine, identifying potential avenues for personalized medicine is just the beginning. Clinical trials are necessary to validate the discussed targets and approaches. As a future direction, partnering with clinicians could help understand whether, and how patients would benefit from such therapeutic methods.[13] The over-representation of people with European ancestry in most data sets also limits generalizability.[13] Investigations require greater diversity to determine whether the same genetic loci are significant across populations and whether epigenetics plays a role in immunotherapy.[13]
Conclusion
As the potential impact of precision medicine for cancer is slowly yet surely being recognized, the work of Dr. Carter and her lab is truly inspiring to passionate researchers. While there is a lot of ground to cover in this battle against cancer, the addition of precision immunotherapy to the arsenal is sure to pave the way for more such meaningful and impactful discoveries in oncology.