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A. 473 patients assessed for eligibility 1 patient COVID-19+ excluded • Decline to participate

472 patients eligible in ONCOVID Trial 378 patients excluded • Negative RT-qPCR • Controls unmatched (age, 95 patients selected for translational gender) with cases research analysis Cancer_FR1_Translational Research (TR)

43 allocated to Control group (TR) 52 allocated to COVID-19 group (TR) No detection of SARS-CoV-2 by: Detection of SARS-CoV-2 by: • RT-qPCR • RT-qPCR (n=50) • Serology • Serology (n=45) • CT-Scan • CT-Scan (n=2)

43 analyzed 35 Cancer_FR1 analyzed for viral shedding (see Figure S2)

34 Cancer_FR1 analyzed for Ct and ALC at diagnosis • Excluded for absence of positive RT-qPCR (n=2) • Excluded for absence ofALC and Ct (n=16) B. C. Mild Moderate Severe S H

S 5(12) 21(50) 16(38) (n=42) COVID--19 10(20) * (n=52) 42(80) H (n=10) 5(50) 3(30) 2(20)

Patients (%) Patients (%) D. E. S H Sym Asym

Sym 32(78) 9(22) (n=41) COVID--19 (n=52) 41(79) 11(21) Asym 10(90) 1(10) (n=11)

Patients (%) Patients (%) F. G. L LA M Mild Moderate Severe

L 5(30) 6(35) 6(35) (n=17) COVID--19 LA 1(9) 4(36) 6(55) (n=52) 24(46) 11(21) 17(33) (n=11)

M (n=24) 4(17) 14(58) 6(25)

Patients (%) Patients (%) Figure S1 A. 52 cancer patients COVI D-19 +

2 cancer pati ents diagnosed by CT-Scan

50 cancer pati ents with at least 2 RT-qPCR (n=210 assa ys)

14 cancer pati ents with time lapse bet ween last positi ve RT-qPCR and first negati ve RT-qPCR > 40 days (n=38 assa ys)

36 cancer patients (n=172 assays) Median durati on of viral sh edding (range) : 35.5 (6-137)

1 canc er pati ent with no ne gati ve RT-qPCR (n=4 assays)

35 cancer pati ents with reli able viral shed ding monitori ng (n=168 assa ys) Median durati on of viral sh edding (range) : 40 days (7-13 7) (see Fi gure 1A-B)

B. 100 HCW COVI D-19 + (n=200 assa ys)

43 HCW with only one RT–qPCR (n=43 assays)

57 HCW with at l east 2 R T-qPCR (n=155 assa ys)

7 HCW with ti me lapse bet ween last positi ve RT-qPCR and first negati ve RT- qPCR > 40 da ys (n=15 assa ys)

50 HCW (n=140 assays) Median durati on of viral sh edding (range) : 21 days (7- 117)

5 HCW with no ne gati ve RT-qPCR (n=22 assays)

45 HCW with R T-qPCR stu dy desi gn identit cal as canc er pati ents (n=118 assays) Median durati on of viral sh edding (range) : 21 days (7-90) ) (see Fi gure 1A -B) Fig ure S2 A. 178 patients included

63 patients excluded • Enrolled in Cancer_FR1 (n=59) • Absence of cancer status (n=4)

115 patients selected for analysis 35 patients excluded • Absence of Ct and ALC at diagnosis and/or reliable viral shedding 80 allocated toCancer_FR1_CR Detection of SARS-CoV-2 by: • RT-qPCR (n=80)

46 Cancer_FR1_CR analyzed forviral shedding

50 Cancer_FR1_CR analyzed forCt and ALC at diagnosis

B. C. S H Mild Moderate Severe

S (n=68) 10(15) 42(62) 16(23) COVID-19 68(85) 12(15) (n=80) H 3(25) 9(75) (n=12)

D. E. S H Sym Asym

Sym (n=66) 55(83) 11(17) COVID-19 (n=80) 66(82)66(82) 14(18)14(18) Asym 1 (n=14) 13(93) (7)

F. G. L LA M Mild Moderate Severe L (n=10) 6(60) 4(40)

10 LA COVID-19 56(70) 14(18) (n=14) 3(21) 6(43) 5(36) (n=80) (12) M (n=56) 10(18) 39(70) 7(12)

Figure S3 A. * * * * ** ** * * * * **** **** 40 **** **** 100 ** **** + ***

30 in cMo 30 + 75 non-cMo o l 20 50 20 HLADR CD14 − + 10 25 10 % Monocytes in CD45 % CD16 0 % CD169 0 0 Ctls Asy m ≤ 20d > 20d Reco very Ctls Asy m ≤ 20d > 20d Reco very Ctls Asy m ≤ 20d > 20d Reco very C. B. ** s ** ) 100 * hi *** * *** + * 10.00

10.00 CD38

75 + + in Neutrophil 1.00

− 1.00 50 in CD19

CD10 0.10

− 0.10 25 ransitional (CD24 % Neutrophils in CD45 0.01 0 0.01 T

Ctls Asy m ≤ 20d > 20d Reco very Ctls Asy m ≤ 20d > 20d Reco very % Ctls Asy m ≤ 20d > 20d Reco very % CD101

D. E. * 0,95 * * * 0,96 * * **** * 0,053 * ** 100. 0 r) 100. 0 100 e it T 10. 0 10. 0 50 Ctls Ctls 1. 0 Asy m Asy m 1. 0 IL-4 (pg/mL)

anti−RBD ( ≤ 20 d ≤ 20 d 30

> 20 d IgM anti−RBD (Titer) > 20 d IgA 0. 1 Rec overy 0. 1 Rec overy Ctls SVS LVS Ctls SVS LVS Ctls Asym ≤ 20d > 20d Reco very

F. G. * * *** ** ** * *** 1e+07 ** * ** 300 * ** 1000 3e+06 100 )

30 100 1e+06 10 IL-6 (pg/mL) 10

Calprotectin (pg/mL) 3e+05 CXCL8 (pg/mL 3 1 Ctls Asym ≤ 20d > 20d Reco very Ctls Asym ≤ 20d > 20d Reco very Ctls Asym ≤ 20d > 20d Reco very H.

* * 50 * *

30 1000

10 100 Legend: IFNγ (pg/mL) 5 Contro l CXCL10 (pg/mL) 10 Ctls Asym ≤ 20d > 20d Reco very Ctls Asym ≤ 20d > 20d Reco very Asymptomat ic

SVS I. LVS * **** ** ** Rec ov ery **** **** *** *** **** ****** * ** ****

o **** ** 1e+02 io 3.00 ** t

1.00 2a ra

α 1e+00 FN

0.30 I /

1 /0.10 CXCL10 rati

1 1e −02 IFNγ 0.03 CCL

Ctls Asym ≤ 20d > 20d Reco very Ctls Asym ≤ 20d > 20d Reco very

Figu re S 4 1 2 3

Ct D0 Symptoms Sev eri ty Age Vir us sh edd ing Gender Cancer status classical monocyt es (CD14 +CD16 low )(cM o) in Mon ocytes Neutrophils in CD45 + CC L11/ CXC L11 CXCL5 CD1 01+CD10 + in Ne utr ophi ls Non-Switched Memory in CD19 + IgD -CD27 - in CD19 + Ig D+CD 27- (Na ive) in CD 19+ Scaled log valu e 4 + + CD19 in CD45 2 no n−c Mo (CD14 lowCD16 +)in Mo nocytes 0 CCL 11/C XCL1 0 −2 IF Nγ/ INFα2a −4 CD16 9-HLA -DR + in cMo Ct_D0 CD 24-IgD+CD 27- (Nai ve) in CD19 + <25 CD24 +IgD -CD27 - in CD19 + >25 Gran zym e B-CD9 5−L - in non-n aiv e CD8 +CD3+ Control na CD2 4high CD 38high (Tra nsi tion al) in CD1 9+ ND CD4 +/CD 8+ in C D3+ Symptoms CD4 + in CD3 + Control Symptomatic PD−1 + in Eom eshigh TCF7 high non- naiv e CD8 +CD3+ Asymptomatic Gr anz yme B+PD−1+ in Eome shigh TC F7high non-na ive CD8 +CD 3+ Seve rity PD −1+ in non−naiv e CD8 +CD 3+ Control Mild + + EM2 in CD8 CD 3 Modera te IgM anti-NC Severe CXCL 11 Age < 65 IFNγ >= 65 CXCL8 Virus shedding CCL 11 Control SVS CCL22 LVS CCL7 na CCL19 Gender TNF α F M CCL26 Cancer status GM-CSF Local Local ly adv anced CCL21 Metastatic Calprotectin CX3CL1 IgG anti-RBD/IgG anti-NC Eomes high TCF7 high in non−n aiv e CD8 +CD3 + Gran zyme B+CD95− L+ in no n-nai ve CD8 +CD3+ Gr anz yme B+ in non-n aiv e CD8 +CD3 + Granzyme B+ in Eomes high TCF7 high non-n aiv e CD8 +CD3+ CD 101 +- CD10+- CD16 - in Ne utr oph ils PD− 1high CXC R5+ in non- naiv e CD4 +CD3+ PD−1 +Granzyme B+ in non−naiv e CD8 +CD3+ CD19 lowCD38 high CD27 + (P lasmab last) in CD 19+ CD3 8+HLA −DR + in non −nai ve CD8 +CD 3+ CD 38+ICOS + in PD −1high CXCR 5+ no n-n aiv e CD4 +CD3 + CD16 9+HLA DR+ in c Mo IFNα2a CXCL10 NK cells in CD45 + CD3 + in CD45 + Lymphocytes in CD45 + Non−naiv e in CD8 + CD3 + CD8 + in CD3 + Non−naiv e in CD4 +CD3 + 7 8 6 3 12 19 58 57 34 29 22 26 31 53 37 32 54 15 38 18 25 50 17 41 55 20 21 14 10 33 36 35 49 91 83 13 47 39 70 40 27 413 201 202 255 193 203 142 258 177 173 106 252 172

Figu re S5 1 2 3

Ct D0 Symptoms Severity Age Virus shedding Gender Cancer status classical Monocytes (CD14+CD16low)(cMo) in Monocytes Neutrophils in CD45+ Calprotectin CD4+ in CD3+ CD4+/CD8+ inCD3+ Granzyme B-CD95−L- in non-naive CD8+CD3+ CCL11/CXCL10 IgG anti-RBD/IgG anti-NC Scaled log value CD101-+CD10-+ CD16- in Neutrophils 4 IgM anti-NC 2 EM2 in CD8+CD3+ 0 −2 + + CD169 HLA-DR in cMo −4 CXCL10 Ct_D0 CX3CL1 <25 IFNγ/INFα2a >25 CXCL8 Control na TNFα ND GM-CSF Symptoms CCL26 Control Symptomatic IFNγ Asymptomatic CXCL11 Severity CCL11 Control Mild CCL22 Moderate CCL19 Severe CCL7 Age < 65 CCL21 >= 65 CD19lowCD38highCD27+ (Plasmablast) in CD19+ Virus shedding CD38+ICOS+ in PD−1highCXCR5+ non−naive CD4+CD3+ Control + + + + RecoveryS VS CD38 HLA−DR in non−naive CD8 CD3 Re covery LVS PD−1+ in EomeshighTCF7high non−naive CD8+CD3+ na PD−1+ in non−naive CD8+CD3+ Gender Granzyme B+PD−1+ in EomeshighTCF7highnon−naive CD8+CD3+ Female Male + + + + PD−1 Granzyme B in non−naive CD8 CD3 Cancer status CD8+ in CD3+ Local + + Locally advanced Non−naive in CD8 CD3 Metastatic Non−naive in CD8+CD3+ NK cells in CD45+ Lymphocytes in CD45+ CD3+ in CD45+ non−cMo (CD14lowCD16+)in Monocytes EomeshighTCF7high in non−naive CD8+CD3+ Granzyme B+ in non−naive CD8+CD3+ Granzyme B+CD95−L+ in non−naive CD8+CD3+ Granzyme B+ in EomeshighTCF7high non−naive CD8+CD3+ PD−1highCXCR5+ in non-naive CD4+CD3+ B cells in CD45+ Non-Switched Memory in CD19+ CD24-IgD+CD27- (Naive) in CD19+ IgD+CD27+ (Naive) in CD19+ CD24-IgD-CD27- in CD19+ CD24highCD38high (Transitional) in CD19+ CD169+HLA-DR+ in cMo IgD-CD27- in CD19+ CD101+CD10+ in Neutrophils CCL11/CXCL11 CXCL5 IFNα2a 6 6 8 3 7 27 70 39 38 54 32 15 41 35 49 37 91 3 33 13 67 50 79 14 30 31 53 55 17 26 25 12 57 19 58 10 29 34 18 83 95 472 443 278 471 202 467 172 462 151 3 193 465 137 201 442 413 423 419 446 473 425 252 427 133 173

Figure S6 A. B. Median overall survival 120 daysvs undefined Median overall survival undefined p=0.002 p=0.348 No of events: 45 No of events: 14 100 100

80 80

60 60

40 40 ALC>0.8G/L & Ct>25 ALC>0.8G/L & Ct>25 ALC<0.8G/L & Ct>25 ALC<0.8G/L & Ct>25 20 ALC>0.8G/L & Ct<25 20 ALC>0.8G/L & Ct<25 (Validation & Discovery) (Validation & Discovery) ALC<0.8G/L & Ct<25 ALC<0.8G/L & Ct<25 Solid Cancer_FR1 & FR3 0 0 0 50 100 150 200 0 50 100 150 200 Hematological Cancer_FR1 & FR3 Days Days 52 41 28 21 6 6 5 4 2 1 34 22 12 8 2 15 12 8 6 1 48 36 12 13 2 10 8 5 4 1 43 20 9 5 1 18 10 7 7 1

Figure S7 A. ** ** ** + 100 * 8 ** + 20

+ 6 15 in CD45 s e 4 10 10

5 2 % NK in CD45

% Lymphocytes in CD45 1 0 0 Ctls Asym ≤ 20d >20d Recovery % B lymphocyt Ctls Asym ≤ 20d >20d Recovery Ctls Asym ≤ 20d >20d Recovery B. ** 50 20 + 40 + 15 30 in CD45 in CD45 10 + 20 + 5 10 Legend: % CD4 % CD8 0 0 Control Ctls Asym ≤ 20d >20d Recovery Ctls Asym ≤ 20d >20d Recovery Asymptomatic

C. SVS

* + ** **** **** LVS 1e+02 ** * 100 ***** ** ** Recovery

+ 1e+01

8 30 D

1e+00 in non-naïve CD8

+ 10

1e−01 % EM2 in C

HLA-DR 3 + 1e−02 Ctls Asym ≤ 20d > 20d Recovery Ctls Asym ≤ 20d >20d Recovery % CD38

Figure S8 Metabolites Virus shedding 4 Category 2 Aze laic ac i d 2-oxovaler ic ac id 0 Docosaned ioic ac i d Anthran ili c ac id −2 Benzo ic ac id PCa e (18:0) −4 Nicot inic ac i d Trigonelline Virus shedding Fructos e Dodecened ioic ac id Arabinos e LVS N-acetylglut amic ac id Succ inic ac id SVS Etherolen ic ac id Carnit ine C8: 1 Carnit ine C6: 0 Category Acetylcarnitine Spermidine ALC < 0.8 & Ct < 25 Undecano ic ac id Hypotaurine ALC > 0.8 & Ct < 25 Docosatetraeno ic ac id Stear ic ac id ALC < 0.8 & Ct > 25 Palmit ic ac id Myrist ic ac id ALC > 0.8 & Ct > 25 Nonadecano ic ac id Nonadeceno ic ac id na Margar ic ac id Pentadecano ic ac id Ela idic ac i d Lino leic ac i d Hexadecadieno ic ac id Heptadeceno ic ac id Palmito leic ac i d Heptadecatrieno ic ac id Behen ic ac id Carnitine Acetylcholine Carnit ine C8: 0 Carnit ine C10: 1 Carnit ine C10: 0 2-hydroxy-3-methylbutyr ic ac id Leucylproline Glucon ic ac id 4-hydroxyproline Homoserine Sebac ic ac id Dimethylarginine Carnit ine C4: 0 Bet aine N6-acetyllysine ; N2-acetyllysine Docosahexaeno ic ac id Arach idic ac i d Hypoxanthine Gamm a glutamyltyrosine Gamm a glutamylleucine Carnit ine C14: 0 Carnit ine C3: 0 PCa e (22:6) PCa e (20:5) Stearidon ic ac id Eicosapentaeno ic ac id Pro line betaine PCa e (22:5) PCa e (20:4) Eicosatrieno ic ac id Arachidon ic ac id Nonano ic ac id 3-indoxy l sulfur ic ac id -3-lact ic ac id Sphingosine-1-phosphat e Tetradecadieno ic ac id Capry li c ac id Tauroursodeoxycholi c aci d Glycoursodeoxycholi c aci d 2-hydroxyglutar ic ac id 2-oxoglutar ic ac id PCa e (18.3) PCa e (14:0) PCa e (16:1) Capr ic ac id Laur ic ac id PCa e (22:4) Glycerol PCa e (20:1) PCa e (18:2) PCa e (20:2) PCa e (18:1) PCa e (17:0) PCa e (15:0) PCa e (16:0) Cho line phosphat e Glycerophosphorylcholine Methylsucc inic ac id Alpha-tocopherol Phosphor ic ac id Cholesterol O-phosphoethanolamine 4-hydroxymande li c ac id Glycerol-3-phosphat e Taurodeoxycholi c aci d Glycodeoxycholi c aci d Citr ic ac id; Isocitr i c ac id Oleic ac id; Ela idic ac id Inosine Fumar ic ac id Taurine Xanthine Trimethyl- Dodecaned ioic ac id Glucuron ic ac id; Galacturon ic ac id Hippur ic ac id Dopamine Thymine Hexadecaned ioic ac i d Tetradecaned ioic ac i d Mannitol Taurochenodeoxycholi c aci d Taurocholi c aci d Glycocholi c aci d Glycochenodeoxycholi c aci d Glycohyocholi c aci d Urac il Adenine 3-hydroxyisovaler ic ac id Glycer ic ac id Pantothen ic ac id Ribose ; Ribulos e Dimethylglycine Beta-hydroxypyruv ic ac id 5-aminovaler ic ac id Niacinamide Glycoli c aci d Xylitol N1,N12-diacetylspermine N1-acetylspermidine 1,3-Dicyclohexylthiourea Cystine Butano ic ac id Propion ic ac id Lysine 2-aminoad ipic ac i d Carnit ine C12: 1 Glycylglycine N-propylamine Glutamine Galactito l; Sorbito l; Mannitol Allant oin Aspart ic ac id Bet a Acet ic ac id Chenodeoxycholi c aci d Ursodeoxycholi c aci d Murideoxycholi c aci d Hyodeoxycholi c aci d Galactose ; ; Mannos e 3-methylhistidine Deoxycholi c aci d Choli c aci d Xylos e 12-dehydrocholi c aci d Ma li c ac id Arabitol Threon ic ac id Erythritol 2-hydroxy-2-methylbutyr ic ac id Ribitol Methylhistidine Inositol Lact ic ac id Alanine Glut amic ac id 5-oxoproline N1,N8-diacetylspermidine N8-acetylspermidine Pyruv ic ac id; Oxaloacet i c ac id GABA 4-hydroxyproline Undecaned ioic ac id Maltose ; Trehalos e Guanosine N1-acetylspermine N-acetylputrescine Adrenaline 3-phenylpropion ic ac id Ur ic ac id Malonylcarnitine Glutarylcarnitine 3-hydroxybutyr ic ac id S-adenosylmethionine Valine Ketoisocapro ic ac id Ketoisovaler ic ac id Glucose-6-phosphat e; Fructose-6-phosphat e Isobutyr ic ac id 2-hydroxybutyr ic ac id N-acetylglutamine Noradrenaline Cystine ; Methylmalon ic ac id Figu re S9 A. Hyodeoxycholic acid 5 5 * * 1.5x10 Ctls 1.5x10 r=0.35, p=0.04 SVS LVS na 5 5 1x10 1x10

Area Corr Area Corr 5 5 0.5x10 0.5x10

0 0 Ctls LVS SVS 0 1 2 3 ALC (G/L) B. Ursodeoxycholic acid 4 10x10 * * r=0.35,p =0.04 Ctls SVS

4 LVS 4 7.5x10 na 7.5x10

4 4 5x10 5x10 Area Corr Area Corr 4 4 2.5x10 2.5x10

0 0 Ctls LVS SVS 0 1 2 3 ALC (G/L) C. N1-acetylspermidine * 6 r=�0.58,p =0.0037 6 2x10 ALC>0.8G/L & Ct>25 2x10 ALC<0.8G/L & Ct>25 ALC>0.8G/L & Ct<25 6 ALC<0.8G/L & Ct<25 6 1.5x10 na 1.5x10 6 1x10 6 1x10 6 Area Corr Area Corr 0.5x10

6 0.5x10 0

6 -0.5x10 Ctls LVS SVS 0 1 2 3 ALC (G/L) D. N1,N12-diacetylspermine

******** r=�0.32,p =0.0097 *** * **** 5 5 10

4 4 10 Area Corr

Log(Area Corr) 3 3 10

Mild Moderate Critical Ctls Mild Moderate Critical 0.3 1.0 3.0 ALC (G/L)

Figure S10