The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy

Abstract

Immunotherapy has revolutionised cancer treatment. However, not all cancer patients benefit, and current stratification strategies based primarily on PD1 status and mutation burden are far from perfect. We hypothesised that high activation of an innate response relative to the adaptive response may prevent proper tumour neoantigen identification and decrease the specific anticancer response, both in the presence and absence of immunotherapy. To investigate this, we obtained transcriptomic data from three large publicly available cancer datasets, the Cancer Genome Atlas (TCGA), the Hartwig Medical Foundation (HMF), and a recently published cohort of metastatic bladder cancer patients treated with immunotherapy. To analyse immune infiltration into bulk tumours, we developed an RNAseq-based model based on previously published definitions to estimate the overall level of infiltrating innate and adaptive immune cells from bulk tumour RNAseq data. From these, the adaptive-to-innate immune ratio (A/I ratio) was defined. A meta-analysis of 32 cancer types from TCGA overall showed improved overall survival in patients with an A/I ratio above median (Hazard ratio (HR) females 0.73, HR males 0.86, P < 0.05). Of particular interest, we found that the association was different for males and females for eight cancer types, demonstrating a gender bias in the relative balance of the infiltration of innate and adaptive immune cells. For patients with metastatic disease, we found that responders to immunotherapy had a significantly higher A/I ratio than non-responders in HMF (P = 0.036) and a significantly higher ratio in complete responders in a separate metastatic bladder cancer dataset (P = 0.022). Overall, the adaptive-to-innate immune ratio seems to define separate states of immune activation, likely linked to fundamental immunological reactions to cancer. This ratio was associated with improved prognosis and improved response to immunotherapy, demonstrating potential relevance to patient stratification. Furthermore, by demonstrating a significant difference between males and females that associates with response, we highlight an important gender bias which likely has direct clinical relevance.

Exploring the impact of body mass index on tumor biology and cancer development

“…Previous studies have also found a high level of variation between tumors and the tumor microenvironment between men and women 41 . However, we do not nd this difference between men and women, when we stratify based on BMI.…”

“…Next, we investigated the composition of in ltrating immune cells using the ratio of adaptive to innate immune cells (A/I ratio). We have previously shown that within tumors the A/I ratio is associated with improved survival 41 . Here, we found that in younger patients with small tumors, obese patients had a higher A/I ratio relative to non-obese patients (P = 0.041) (Fig.…”

Biophysical and biochemical aspects of immune cell–tumor microenvironment interactions

“…Moreover, the concentration of adaptive immune cells relative to innate immune cells is variable across genders, further complicating the universality of immune-based cancer interventions. 103,104 Despite the complex biochemical signals and biophysical properties, T cell-based therapy remains a promising area of interest, especially compared to components of the innate immune response that have more varied effects on tumors. Such evidence indicates that CD8+ and CD4+ T cells are an important and effective component of the adaptive immune response to tumor cells, with recent efforts working to overcome limitations on their effectiveness.…”

Enhancing Therapeutic Efficacy and Safety of Immune Checkpoint Inhibition for Bladder Cancer: A Comparative Analysis of Injectable vs. Intravesical Administration

“…Bladder cancer (BC) is the second most prevalent neoplasm of the urinary tract, with an estimated US prevalence of a million cases and an alarming recurrence rate of 75-80% after initial transurethral resection of exophytic tumor (TURBT) [1]. The average age at onset of BC is 74 years [2] with a fourfold higher prevalence of BC in males compared to females [3].…”

“…The interplay of innate and adaptive immune cells between genders potentially influences BC prevalence, prognosis, and response to immunotherapy, which underscores the necessity for tailored treatment approaches [3]. A lower BC prevalence in females [4] may be mechanistically linked to the antitumor effect triggered by recurrent stimulation of innate immune cells by bacteriuria [5] and the resultant urothelial exfoliation may be inadvertently getting rid of [6] precancerous urothelium cells in females.…”