The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy.
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...
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2023-01-01
|
| Series: | PLoS ONE |
| Online Access: | https://doi.org/10.1371/journal.pone.0281375 |
| _version_ | 1811167163387478016 |
|---|---|
| author | Johanne Ahrenfeldt Ditte S Christensen Andreas B Østergaard Judit Kisistók Mateo Sokač Nicolai J Birkbak |
| author_facet | Johanne Ahrenfeldt Ditte S Christensen Andreas B Østergaard Judit Kisistók Mateo Sokač Nicolai J Birkbak |
| author_sort | Johanne Ahrenfeldt |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-04-10T16:05:40Z |
| format | Article |
| id | doaj.art-2e10a8146a224eb3bc42295f9af6be36 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-04-10T16:05:40Z |
| publishDate | 2023-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-2e10a8146a224eb3bc42295f9af6be362023-02-10T05:31:26ZengPublic Library of Science (PLoS)PLoS ONE1932-62032023-01-01182e028137510.1371/journal.pone.0281375The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy.Johanne AhrenfeldtDitte S ChristensenAndreas B ØstergaardJudit KisistókMateo SokačNicolai J BirkbakImmunotherapy 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.https://doi.org/10.1371/journal.pone.0281375 |
| spellingShingle | Johanne Ahrenfeldt Ditte S Christensen Andreas B Østergaard Judit Kisistók Mateo Sokač Nicolai J Birkbak The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy. PLoS ONE |
| title | The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy. |
| title_full | The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy. |
| title_fullStr | The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy. |
| title_full_unstemmed | The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy. |
| title_short | The ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy. |
| title_sort | ratio of adaptive to innate immune cells differs between genders and associates with improved prognosis and response to immunotherapy |
| url | https://doi.org/10.1371/journal.pone.0281375 |
| work_keys_str_mv | AT johanneahrenfeldt theratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy AT ditteschristensen theratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy AT andreasbøstergaard theratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy AT juditkisistok theratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy AT mateosokac theratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy AT nicolaijbirkbak theratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy AT johanneahrenfeldt ratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy AT ditteschristensen ratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy AT andreasbøstergaard ratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy AT juditkisistok ratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy AT mateosokac ratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy AT nicolaijbirkbak ratioofadaptivetoinnateimmunecellsdiffersbetweengendersandassociateswithimprovedprognosisandresponsetoimmunotherapy |